Oral & Craniofacial Sciences Graduate Group Faculty
One in three American adults suffers from arthritis symptoms, yet the molecular basis of this degenerative skeletal disease remains unclear. Our research focuses on the molecular pathways controlling mesenchymal stem cell differentiation, how these pathways function in normal skeletal tissue, and how they can be harnessed to repair tissue damaged in degenerative skeletal disease. To answer these questions, we combine molecular, cellular, physiological, and materials science approaches. I believe this interdisciplinary strategy will lead to the identification of targets to prevent skeletal disease or to improve skeletal repair.
A current focus is to understand the mechanisms by which TGF-beta regulates osteoblast and chondrocyte differentiation. Cell-based studies are used to identify signaling pathways and transcription factors downstream of TGF-beta. In vivo studies allow examination of the role of these pathways in bone and cartilage. A key goal of this work is to understand the control of skeletal matrix formation and quality.
Dr. Armitage's current research interests include the development and testing of new methods for the diagnosis and treatment of periodontal diseases. Ongoing studies include evaluation of (1) microbial diversity in the subgingival flora, utilizing 16S ribosomal RNA gene detection techniques (in collaboration with Drs. David Relman and Paul Lepp of Stanford University); (2) salivary sialyl Lewis X in risk assessment for periodontal disease (in collaboration with Drs. Susan Fisher and Akraporn Prakobphol); (3) the effects of bisphosphonates and parathyroid hormone on mandibular bone density (in collaboration with Drs. Nancy Lane, Department of Medicine, School of Medicine, and Sharmila Majumdar, Department of Radiology, School of Medicine); (4) genetic tests for susceptibility to periodontal infections; and (5) drug-delivery systems for the treatment of periodontitis.
Research techniques routinely employed include (1) clinical research methods for the collection and analysis of periodontal examination findings; (2) gingival crevicular fluid analyses; (3) periodontal microbiology techniques such as the collection of subgingival plaque samples for microscopic, cultural, and molecular analyses; and (4) clinical trials and research study design.
Dr. Barber’s research program addresses fundamental questions on how cell behaviors are regulated, with an emphasis on differences between cancer and normal cells. Her work is at the interface of cell signaling and cell biology, with a current focus on cancer cell behaviors. Her group uses a number of different cell and animal model systems to investigate proliferation, glycolytic metabolism and migration of mammalian cells, chemotaxis of Dictyostelium cells, and dysplasia in Drosophila. They are asking how distinct signaling networks regulate these behaviors, with an emphasis on post-translational modification of proteins by protonation and by phosphorylation. An innovative aspect of Dr. Barber’s research is revealing how dynamic changes in intracellular pH (pHi) drive cell processes, such as cytoskeleton remodeling for cell migration, cell cycle progression for cell proliferation, and enzyme localization and activity for glycolytic metabolism. In collaborations with Matthew Jacobson (computational biology) and Mark Kelly (NMR spectroscopy) at UCSF their work highlights how protonation acts as a post-translational modification regulating protein structure and function (Schonichen et al., 2013 Ann. Rev. Biophysics 42:289). They are determining the structural design principles and functional significance of pH sensors, or proteins with activities or ligand-binding affinities that are sensitive to physiological changes in pH. Focusing on pHi-dependent cell behaviors they identified mechanisms of pH sensing by proteins regulating cell polarity (Frantz et al., 2007 J. Cell Biol. 179:403), actin filament assembly (Frantz et al., 2008 J. Cell Biol. 183:865), and focal adhesion remodeling (Srivastava et al., 2008 Proc. Natl. Acad Sci. 105:14436; Choi et al., 2013 J. Cell Biol. 202:849). As they recently described (Webb et al., 2011 Nat. Rev. Cancer 11:671), increased pHi is a hallmark of most cancers, which highlights the clinical significance of understanding how pHi dynamics regulates cell behaviors.
The Brückner lab uses the genetic model organism Drosophila melanogaster to address questions relevant for mammalian development, tissue homeostasis and human disease.
(1) Cleft palate and metastasis of oral cancers are two major problems in oral health that are caused by the deregulation of the processes of epithelial plasticity (EP) or epithelial-to-mesenchymal transition (EMT). In many cases of EP and EMT, Transforming Growth Factor-β (TGF-β) or Bone Morphogenetic Protein (BMP) cooperate with Akt signaling, but the molecular basis remains incompletely understood. Based on an RNAi screen, expression profiling and ChIP analyses in a cell-based Drosophila model, we determine the mechanism of cooperation between BMP and Akt signaling, for which we particularly focus on the differential binding of transcriptional targets.
(2) Cell proliferation, survival and differentiation are commonly known to be regulated by stereotyped developmental programs and physiological feedback mechanisms. However, far less is understood how extrinsic sensory stimuli modulate the signaling and responses of cells and tissues, representing a missing link in animal development and tissue homeostasis. To address this problem, we use a simple Drosophila model for niche support by the PNS, which focuses of the hematopoietic system as a target tissue. The model takes advantage of the hematopoietic pockets (HPs) in the body wall of the optically transparent Drosophila larva, where blood cells (hemocytes) reside in direct physical contact with segmentally repeated sensory PNS clusters and functionally rely on the PNS. Our lab investigates the cellular and molecular mechanisms by which constitutive and neuronal activity-dependent PNS ‘circuits’ regulate hematopoiesis and blood cell homeostasis.
The lab studies basic mechanisms by which signaling between cells coordinates morphogenesis. Understanding this control has significance beyond its fundamental importance in development since birth defects are the leading cause of death for infants during the first year of life. Craniofacial anomalies are the most common class of congenital defect in humans, with three quarters of all malformations identified at birth involving craniofacial dysmorphogenesis. We utilize multiple approaches based in mouse genetics to understand fundamental signaling processes as they relate to development. In addition to targeted and conditional gene disruption in mice, we are generating mice harboring targeted point mutations that disrupt specific signal transduction pathways. By integrating these in-vivo approaches with mass spectrometry-based phospho-proteomics, cell biology and biochemistry, we seek to understand the mechanistic basis of signaling control of craniofacial development.
One ongoing project focuses on a disease called craniofrontonasal syndrome (CFNS), an X-linked congenital disorder that includes a number of craniofacial, skeletal, and neurological malformations and is caused by mutations in the ephrin-B1 gene. Mice with mutations in the ephrin-B1 gene display strikingly similar phenotypes to human CFNS patients, underscoring the value of the mouse as a model for studying congenital disease. Ephrin-B1 is a member of a unique family of signaling molecules that can signal by multiple distinct molecular mechanisms. By using gene targeting in ES cells to generate mice harboring a series of signaling mutations in ephrin-B1, we learned that distinct CFNS malformations are controlled by different signal transduction pathways.
We have also integrated a mass spectrometry-based phospho-proteomic approach to identify signal transduction components of the Eph/ephrin signaling pathway in craniofacial development. The signaling network by which Eph/ephrin signaling controls craniofacial development is a topic of ongoing study in the lab.
My research is focused on the hormonal and ionic controls of mineral homeostasis and skeletal development using molecular, transgenic, and gene knockout approaches. Specifically, we study the actions of parathyroid hormone receptor (PTH1R), insulin-like growth factor-1 receptor (IGF1R), and the extracellular Ca2+-sensing receptor (CaSR) in tissues that control mineral metabolism and bone growth. We have generated mice with conditional ablation of the PTH1R, CaSR, or IGF1R genes in parathyroid glands (PTGs), kidney, intestine, cartilage, bone, skin, pituitary gland (Pit) and/or hypothalamus then examined their functional outcomes. We also developed primary cell/organ cultures to allow for genetic or pharmacological manipulations of the cell/organ in vitro for mechanistic studies. Our data demonstrated that PTH1R, IGF1R, and CaSR play non-redundant roles in the growth, survival, and differentiation of chondrocytes and bones cells and eventually overall bone growth. We also unveiled distinct roles of the CaSR in modulating parathyroid hormonal secretion in PTGs, Ca2+ recycling in kidney, Ca2+ absorption in guts, keratinocyte differentiation in skin, and general growth and energy metabolism through CaSR actions in the Pit and hypothalamus. Research is ongoing to explore the mechanisms underlying the above actions. We have also begun to use some of the above animal models to investigate the role of the CaSR and IGF1R in the healing of bone fractures and the repair of cartilage injuries due to excess mechanical loading. There is the potential of using these receptors as new therapeutic targets for metabolic and skeletal diseases.
The focus of my research program is the genetics and epidemiology of human autoimmune disease, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). My research unit has devoted substantial effort to the performance of genome wide association (GWA) and other genetics studies, which have led to the identification of over 30 genes that contribute to risk and outcome of these disorders. This work has also highlighted key biologic pathways responsible for disease onset and progression, which can inform more basic research to define the mechanism of these genetic associations. Given the heterogeneity of these disorders, we are also devoting substantial effort to the refinement of genotype-phenotype associations, such as the specificity of genetic associations for serologic or clinical subphenotypes. Several genes we have been studying, including STAT4 and TNFAIP3, are also of interest due to emerging evidence supporting their association with multiple autoimmune disorders and phenotypes. Given the strong association of the major histocompatibility complex (MHC) region with multiple autoimmune disorders, we are performing fine mapping studies of this region in order to further define the complex genetic associations of this region with SLE, RA and related phenotypes. We are also pursuing studies designed to better understand ethnic differences in autoimmune disease risk and outcome. Lastly, we have initiated several recent studies that seek to define the contribution of epigenetic factors, particularly DNA methylation patterns, to autoimmune disease risk and outcome.
Cynthia Lee Darling has been a researcher in the field of biomedical photonics for the past twelve years and has published over 70 papers in this area. The focus of her research program is to incorporate polarimetric imaging techniques to completely describe the interaction of polarized light with dental hard tissues. Students in her research group have been able to investigate: the optical properties of developmental defects in the near-infrared, employed near-infrared imaging to monitor laser ablation through dental enamel in real-time to directly visualize peripheral thermal and mechanical damage, and explored the image contrast of dental caries at other near-infrared wavelengths besides 1300-nm.
The focus of research in the Den Besten laboratory is in the biomineralization of tooth enamel and dentin. They currently have several active projects to study various aspects of enamel and dentin biomineralization. One of these projects aims to determine the mechanism by which fluoride affects enamel formation to result in enamel fluorosis. In this project they are investigating several possible mechanisms by which enamel fluorosis occurs, including altered protein/mineral interactions, and a direct of fluoride on the developing ameloblasts.
In order to determine factors that alter enamel formation, we need to better understand the proteins, proteinases and other molecules responsible for normal enamel formation. We are using immunopertrubation and antisense methods in tooth organ culture to alter the presence of certain proteins in enamel development. These studies have suggested that the enamel matrix protein, ameloblastin, has a key role in the regulation of enamel matrix synthesis.
Their studies on dentin formation have utilized various available transgenic mouse models with transgene expression driven by the osteocalcin promotor. In one of these mice models that over expresses TGF- , the dentin mineral apposition rate is increased while the physical properties of the dentin remain the same. Studies of dentin formation in these various transgenic mouse models will allow us to determine the key elements in dentin biomineralization and to use these elements to form dentin-like materials in vitro .
Research in the Derynck lab focuses on the role of transforming growth factors- and , two structurally unrelated growth and differentiation factors, in mesenchymal and epithelial cells. We use molecular, genetic cell biological and biochemical approaches to address several cell physiological and developmental questions. The work has direct relevance to many questions in orofacial development and healing and is therefore of value to the proposed NRSA.
TGF- is a growth factor for many cell types of non-hematopoietic origin and exerts its functions in an autocrine/paracrine fashion mainly in normal epithelia and in solid tumor development. It is present as a transmembrane protein at the cell surface, from which the ecodomain can be proteolytically released as a secreted polypeptide. The transmembrane form of TGF- functions as a growth factor involved in cell-cell communication. Our major projects focus on the role of the cytoplasmic domain. We specifically study its ability to interact with cytoplasmic proteins that constitute an associated protein kinase complex and its potential role as a signaling entity, as well as its function in cell physiology and development.
TGF- is a growth and differentiation factor which induces growth arrest in epithelial cells, yet stimulates proliferation in mesenchymal cells, and furthermore, is a potent inducer of extracellular matrix deposition and integrin expression. TGF- is a prototype factor for the many related differentiation factors in the TGF- superfamily. Two major lines of research are followed. In one large project, we address the mechanism of signaling of the TGF- receptors, which are transmembrane serine/threonine kinases. In the other major project, we study the role of TGF- and vgr-1, a related factor, in mesenchymal differentiation, specifically in differentiation into the muscle, bone and cartilage lineages. These developmental questions are approached in cell culture andin vivo, including transgenic models.
Our research applies microscale and nanoscale technologies to create new and improved ways to deliver medicines to target sites in the body and to enable the body to heal itself. Our work is based on the idea that if we can understand and manipulate the world at the microscale and nanoscale, we can engineer biomedical technologies that interact directly with cells, drugs, and biomolecules.
During cell division, each daughter cell must inherit exactly one copy of the chromosome. Errors can lead to cell death or cancer in somatic cells, and developmental disorders in the germline. How does the cell integrate biochemical and mechanical processes to ensure that its genetic material is equally distributed to daughter cells? While we have a nearly complete list of molecules essential to cell division, we know very little about the underlying mechanical interactions and principles. The Dumont Lab aims to understand how cells generate, detect, and respond to mechanical forces to accurately segregate their chromosomes, and how mechanical and biochemical information is integrated for cellular decision making.
Two macromolecular machines coordinate chromosome segregation: the μm-scale spindle moves chromosomes through its growing and shrinking microtubules, and the 100nm-scale kinetochore anchors chromosomes to spindle microtubules and regulates their segregation. How do these two machines precisely and robustly divide chromosomes, and how do their nm‐scale constituents work together to generate μm-scale movements?
Our work focuses on the basic requirements of accurate chromosome segregation: moving chromosomes, and moving them to the right places. How do shrinking and growing microtubule tips generate force to move chromosomes, and how do chromosomes hold on to such dynamic structures? Furthermore, how can the spindle be strong enough to oppose these forces, and yet dynamic enough to remodel itself as chromosomes move? Finally, how does the cell verify that chromosome copies are correctly attached to the spindle prior to segregating them, such that its genetic material will be equally distributed to daughter cells?
To address these questions, one must uncover how molecules, mechanics and cellular function relate to each other. We thus use an inter-disciplinary approach. We probe key players using cell and molecular tools, map how the cell’s machines are organized and designed using sub-pixel resolution imaging, and mechanically perturb cells by cutting their structures and poking them. Together, our work will build fundamental knowledge in how mechanical and chemical processes are integrated over cellular length scales, and in life processes that, if perturbed, cause disease.
The Featherstone lab is currently involved in research in the following fields:
1.Effects of Lasers on Dental Hard Tissues
The overall objective of this research is to provide fundamental information about the effects of laser light on dental hard tissues (enamel and dentin of the teeth) in order to develop means of using lasers to a) detect early decay, b) treat teeth and modify the mineral for the prevention of the progression of dental decay.
2.Management of Dental Decay by Risk Assessment
These studies involve the application of microbiological and chemical assays of saliva as part of a risk assessment scheme to enable the management of dental decay by prevention and conservative treatment rather than conventional physical removal of decay and placement of restorations (fillings).
3.Biological mineral and protein interactions
Biological mineral is a defective calcium phosphate crystalline material. Studies of protein/mineral interactions are in progress to understand the processes of biomineralization.
NRSA trainees can participate in scientific and laboratory aspects ofany of the above areas, dependent on their background and interests.
The Fisher lab's major area of investigation is understanding adherence mechanisms used by microbial pathogens. In one project we are testing the hypothesis that bacteria which colonize the oral cavity do so by interacting with the carbohydrate portions of salivary receptors. In general, we use whole-cell ligand blotting (overlaying blots of salivary glycoproteins with bacteria) to identify interactions between individual salivary molecules and particular bacterial species. This technique led to the identification of a highly glycosylated, proline-rich glycoprotein (PRG) as the major Fusobacterium nucleatum receptor in saliva. We then determined, using mass spectrometry and nuclear magnetic resonance spectroscopy, the complete structure of the subset of PRG oligosaccharides that carry the bacterial receptor activity. We used this same experimental strategy to study the interaction between streptococci and the low-molecular-weight salivary mucin. Very recently we showed that this glycoprotein carries sulfated sialyl Lex structures and is a ligand for L-selectin. This observation has interesting implications for leukocyte trafficking in the oral cavity.
Optical or photonics based methods are playing an increasingly important role in medicine and dentistry by providing a means of minimally invasive diagnostics and imaging without the use of ionizing radiation. Projects include: the use of optical diagnostic tools such as optical coherence tomographic imaging, Raman scattering, IR and fluorescence imaging, and time-resolved photothermal radiometry. In order to use lasers and optical diagnostic tools safely and effectively it is important to characterize the optical properties of the tissue at the wavelengths of interest. Therefore, a major emphasis of the research of the Fried lab has been on the accurate elucidation of those properties.
Stuart Gansky's research has concentrated on collaborative oral health research areas and its related methodological issues. Collaborative research projects have included a series of studies examining dentin, bonding, and tissue engineering; the Intergenerational Study of Adult Periodontitis (MultiPied); the Study of Chronic Pain/Temporomandibular Disorders (TMDs) in Young Women; caries risk assessment studies (one on early childhood caries and one on high risk adults); and tobacco cessation interventions.
He currently serves as Associate Director of the Biostatistics and Research Design Core of UCSF's Comprehensive Oral Health Research Center of Discovery as well as Director of the Measurement & Evaluation Core of UCSF's Center to Address Disparities in Children's Oral Health. He is PI of an NIDCR grant to develop risk assessment models for early childhood caries. Also, he is co-PI and biostatistician to study factors related to temporomandibular joint disorders and fibromylagia precursors in an established cohort of young women in which racial differences in pain reports have been found.
Our lab seeks to understand how specific oncogenes alter the cell cycle, miRNA and metabolic signaling pathways to drive tumorigenesis. We study how cancer signaling pathways are activated in breast and liver cancers and hematopoietic malignancies, amongst the most prevalent and deadly forms of human cancer. We are particularly focused on the MYC oncogene, the downstream pathways it activates, and synthetic-lethal strategies to target MYC ove-rexpressing cancers. Using a variety of model systems we seek to develop anti-cancer therapeutics to selectively inhibit cancer signaling pathways.
"My areas of interest include clinical, laboratory, and epidemiological studies relating to the oral manifestations of AIDS; the oral effects of cancer therapy; and the development of new therapeutic approaches for oral mucosal and salivary gland disease. I am part of a major epidemiological study of the oral lesions of HIV infection and direct a group of investigators identifying the oral lesions and providing treatment to people with these lesions. Some current studies include the following: the prevalence, incidence, and predicators of oral lesions in women with HIV infection (as part of the Women's Interagency HIV Study -WIHS), and the changing patterns of oral disease in the era of highly active antiretroviral therapy in different HIV-positive populations. In addition, I am collaborating with Dr. Francisco Ramos-Gomez (Dept. of Growth & Development) on studies of injuries to dental heath-care workers.
I am involved in several clinical drug trials, including the treatment of aphthous ulcers, the treatment of oral warts, and the use of antifungal medications in the treatment of oral candidaisis. In the future, I plan to continue with my work in all of these fields, to learn more about the significance of the oral lesions of HIV infection and to develop better drugs for the treatment of a variety of oral conditions, such as oral candidasis, warts, xerostomia, and aphthous ulcers."
My major scholarly and clinical interest for the last thirty-plus years has been the impact on the mouth and on the health sciences of HIV and AIDS. This has led to a focus on broader aspects of global health sciences, oral issues and AIDS being the most significant to me. My colleagues and I have been privileged to make contributions that have been of broad significance in the diagnosis and care of patients with HIV infection. This work has brought me into contact with a wide array of people, problems and issues worldwide in academic and community health care, in basic, clinical and social/behavioral biomedical science as well as in industry. This has extended into the political arena statewide, nationally and internationally as we have sought and defended funding for research work in our field and for dental and medical research in general, for care for HIV-infected people and concerning broader issues of neglect, stigma, poverty and disparity in global health. My leadership roles in UCSF’s AIDS activities culminated in my becoming Director of the campus-wide AIDS Research Institute 2003-2012. My work has led to extensive media contact, including television, radio and the press and I have learned to respect their role in presenting our work to the public. Similarly, I have come to work with and develop mutually supportive relationships with community representatives and groups, including activists. I have been able to continue my research while assuming significant administrative responsibilities and have ventured into areas of global health beyond my original focus on oral health and on AIDS. I have been very active in the growing Global Health Sciences Program at UCSF and also led for seven years the Sjögren’s Syndrome registry [SICCA].
As Associate Dean for Global Oral Health, indeed in most of my leadership roles, I offer a bridge between Dentistry and the other health sciences and ensure that our field both takes innovation and momentum from the mainstream while contributing to it in many ways. I try to bring elements of that set of experiences and skills to bear on elevating the relevant programs of the School to their rightful place of preeminence, identify and nurture new investigators and clinician scholars in oral global health and foster new initiatives.
Stefan Habelitz is a Materials Scientist and Chemist and Associate Professor at the Department of Preventive and Restorative Dental Sciences at the School of Dentistry at UCSF. His research focuses on understanding how matrix proteins control mineralization in enamel and dentin. Current approaches include: 1. Remineralization of Dentin Caries Lesions: Anionic polymers, like Poly-Aspartic Acid, are used to induce intrafibrillar mineral within collagen fibrils. This project attempts to recover lost dental tissue function by a mineralization process, (see, Burwell et al. PLOS-One 2011). 2. Mimicking Enamel Formation In-Vitro: Our recent studies in the lab have shown that amelogenin can self-assemble into ribbons which self-align and form an organic matrix mimicking the organization of apatite nanofibers in dental enamel. In this project we attempt to induce apatite crystallization on amelogenin templates to obtain materials similar to enamel (Martinez-Avila et al., Biomacromolecules 2012). 3. Micropatterned Porous Membranes for Dental Tissue Synthesis: In this project we designed a variety of porous membranes that enable the precise positioning of cells thus facilitating cellular organization similar to odontoblasts at the pulpal wall. We study the potential of these membranes for in-vitro synthesis of dentin and enamel using dental stem cells, embryonic stem cell and iPS cells.
Mechanical loads manifest into strains within tissues and interfaces of an organ. Strains within tissues are transduced by the cells to produce the needed extracellular matrix proteins to meet functional demands. This is the general philosophy of research in my laboratory which is within the Division of Biomaterials and Bioengineering. Our lab has a strong focus on mechanics, materials, and investigating adaptation of tissues/interfaces through spatiotemporal mapping of “mechano-responsiveness”. This is done by correlating mechanical strain induced biochemical signals at soft-hard tissue interfaces using several model systems including the bone-ligament-tooth fibrous joint. Due to the interdisciplinary nature of research, my laboratory is extended to the Molecular Foundry of Lawrence Berkeley National Laboratory, and Stanford Synchrotron Radiation Lightsource (SSRL) at Stanford Linear Accelerator Center (SLAC) with the help of NIH and DOE funded/peer-reviewed proposals. Mapping of biochemical expressions, physical properties of load bearing tissues, and biomechanics of organs are performed at UCSF, and as a guest scientist at the national laboratories/facilities.
Dr. Hsiao’s research focuses on understanding how hormone and regulatory signals control mesenchymal tissues in normal growth and in disease. His current projects focus on the skeletal system, and include developing a new mouse model for studying G-protein signaling in bone growth and developing human induced pluripotent stem cell (iPSC) models for human genetic bone diseases. By using a wide spectrum of patient-inspired approaches, he hopes to develop a broader understanding of the biology underlying human skeletal development. This new knowledge will help us devise novel therapeutic approaches for treating human skeletal disorders and bone injuries and examine how hormone signals affect other mesenchymal tissues such as fat, muscle, cartilage, and blood vessels.
Dr. Hsiao received his BA magna cum laude in biochemistry and molecular biology from Harvard University. Dr. Hsiao completed his MD and PhD at the Johns Hopkins Medical School. After completing his internal medicine residency at Johns Hopkins, Dr. Hsiao came to the UCSF for his endocrinology fellowship. He is currently an assistant professor at UCSF. Dr. Hsiao is a former California Institute of Regenerative Medicine Clinical Scholar at the Gladstone Institute of Cardiovascular Disease. His work has been recognized by a 2007 Young Investigator Award from the American Society for Bone and Mineral Research, a a 2008 National Osteoporosis Foundation research grant award, and a 2012 March of Dimes Basil O’Connor Starter Award.
As a clinician scientist, my main goals are to conduct basic science/clinical research and to someday translate the findings directly to patient care. As an American Association of Endodontists Educator Fellow, my other focus is to optimize the educational experience in endodontics for dental students and residents. Currently, my research efforts involve the following in collaboration with several faculty members in the Behavioral Sciences, Biomaterials and Bioengineering, Oral Epidemiology and Public Health Dentistry Divisions within the Department of Preventive and Restorative Dental Sciences:
1) Basic science: understanding the molecular mechanism of bacterial pathogenesis in root canal infections and elucidating the process of periapical bone breakdown upon endodontic infection using cell-based and invivo studies
2) Prevention: defining the risk factors to pulpal injury through case-control studies
3) Therapy: developing a novel method for crack-tooth repair
4) Educational: unraveling the stress components in clinical endodontic training from observational studies
I serve as the interim Chair of the Division of Oral Epidemiology and Dental Public Health. The Division provides a population and community-based approach to the oral health sciences, and is the home to the post-graduate programs in Dental Public Health (directed by Dr. Howard Pollick), Fellowship in Geriatric Dentistry (details below), and Masters of Science degree in Dental Hygiene program (directed by Dr. Margaret Walsh). As the Interprofessional Education Faculty Lead for the School of Dentistry, I collaborate with the Faculty Leads from the other Schools to develop didactic, clinical, and elective curricula for all UCSF health professions students, in addition to a massive open online course (MOOC) which will be available world-wide. I am the Director for Dentistry of UCSF’s Multidisciplinary Geriatrics Fellowship in Dentistry, Medicine, and Mental/Behavioral Health. This two-year training program provides interdisciplinary, team-based clinical, education, leadership, and research training in the care of older adults, with a focus on underserved populations.
My research interests lie in understanding the development of teeth and orthodontic tooth movement. This involves a wide spectrum of questions such as:
How do teeth form? Are there other functions of teeth besides mastication, particularly in systemic health? Can teeth be used as diagnostic markers of systemic disease? How do teeth move within the alveolar bone during eruption and orthodontic treatment? Can we induce human teeth to grow continuously like rodent incisors? The answers to such questions may lead to improvements in the prevention, diagnosis, and/or treatment of dental-related problems in the clinic.
We have generated several mouse models with fascinating tooth phenotypes and are currently uncovering the molecular mechanisms responsible for the phenotypes. We also have numerous mouse studies underway looking at the roles of soft and hard food diets on craniofacial morphology, the effects of inferior alveolar nerve block on third molar agenesis, and gene expression profiling during orthodontic tooth movement.
Dr. Jordan is a pathologist with a research interest in oral and head and neck cancers. He is active in the Radiation Therapy Oncology (RTOG) group where he co-directs the RTOG Biospecimen Repository. The RTOG is one of 11 co-operative cancer groups that conduct large multi-institution clinical trials of cancer therapies and is responsible for several major advances in the management of head and neck, GU and brain cancers. In this capacity he serves as the pathology Chair for several clinical trials. In addition he has contributed to recent studies identifying the important role the human papilloma virus (HPV) plays in a subset of head and neck cancers. His own research is focused on understanding the molecular basis of oral cancer and its precancerous forms using novel molecular assays.
We are interested in the molecular biology of sensory transduction and neurotransmitter action in the mammalian nervous system. One of our goals is to understand the molecular basis of somatosensation - the process whereby we experience touch and temperature - with an emphasis on identifying molecules that detect noxious (pain-producing) stimuli. We are also interested in understanding how somatosensation is altered in response to tissue or nerve injury.
Our approach has been to identify molecular targets for drugs or natural products that mimic the psychophysical effects of commonly encountered somatosensory stimuli, such as heat or cold. Thus, we have asked how capsaicin, the main pungent ingredient in "hot" chili peppers, elicits a sensation of burning pain. Using a combination of molecular genetic, electrophysiological, and histological methods, we have shown that capsaicin activates an excitatory ion channel (called TRPV1) on sensory nerve endings. Remarkably, TRPV1 is also activated by heat (>43¼C), and we have used transgenic methods to demonstrate that this channel contributes to the detection of noxious heat in vivo and is essential for the development of thermal hypersensitivity following tissue injury. These findings have led us to ask how TRPV1 functions as a molecular integrator of physical and chemical signals that regulate sensory neuron excitability under normal and pathophysiological conditions.
On a related front, we have extended our molecular analysis of somatosensation by determining how we detect cold. Following the paradigm set forth by our work on the capsaicin receptor, we asked how cooling compounds, such as menthol, elicit a cool sensation. We have cloned a menthol receptor from primary sensory neurons and shown that it is also activated by cold thermal stimuli, proving that menthol elicits its familiar psychophysical sensation by activating a cold receptor. The structure of this menthol/cold receptor (TRPM8) resembles that of TRPV1, demonstrating that ion channels of this class serve as the principal sensors of thermal stimuli in the mammalian peripheral nervous system. Indeed, we have recently shown that mice deficient in TRPM8 display striking defects in cold and menthol sensitivity at the cellular and behavioral levels.
In more recent studies, we have identified another TRP channel (ANKTM1 or TRPA1) on sensory nerve fibers that is activated by allyl isothiocyanate, the pungent ingredient in wasabi and other mustards. Genetic and physiological evidence from our lab suggests that TRPA1 is an important component of the signaling mechanism through which certain pro-algesic agents depolarize sensory neurons to produce pain hypersensitivity and neurogenic inflammation.
In addition to our work on somatosensation and pain, we also study specific neurotransmitter receptor systems, such as those activated by serotonin or extracellular nucleotides. A recent example of our work in this area includes identification of the P2Y12 receptor, an ADP-activated G protein-coupled receptor that contributes to platelet aggregation and serves as the molecular target for the widely prescribed antithrombotic drugs, clopidogrel and ticlopidine. P2Y12R is also expressed by microglial cells in the brain and we have recently shown that this receptor modulates microglial activity to regulate injury responses in the central nervous system.
Obesity is a major risk factor for metabolic disorders such as type-2 diabetes and cardiovascular disease. Adipose tissues serve as central regulators of energy homeostasis in response to a variety of environmental and genetic factors, by systemic signaling via secretion of various adipokines, and by adaptive thermogenesis. The main focus of our lab is to uncover the molecular circuits that control fat cell development and function by employing a wide range of molecular biology, developmental biology and biochemical approaches.
All mammals including humans harbor two types of adipose tissue that serve distinct physiological functions: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT functions mainly in the storage of excess energy, while BAT specializes in dissipating energy in the form of heat through a process called non-shivering thermogenesis, and functions as a defense against hypothermia and obesity. Due to its remarkable oxidative capacity to dissipate excess chemical energy, decreased BAT mass is closely linked to the development of obesity and metabolic disorders. Since recent studies clearly demonstrated the existence of active BAT depots in adult humans, altering the amount and activity of BAT could provide a novel therapeutic intervention to counteract obesity and metabolic syndrome.
Over the last several years, we have been studying the transcriptional regulation of brown fat development. We have recently defined PRDM16 (PR-domain containing 16) and C/EBPβ as a critical transcriptional unit that determines the cellular fate of brown fat. Significantly, ectopic expression of the two factors is sufficient to reconstitute a fully functional brown fat program in naïve fibroblastic cells, from mouse and man, in vivo.
Our goal is to further decode the transcriptional and epigenetic regulatory networks that govern fate determination and maintenance of brown fat cells, and to investigate their roles in controlling whole body energy metabolism. We hope these studies have applications to the development of novel therapies for obesity, insulin resistance and metabolic diseases.
Embryonic development is one of the most beautiful processes in nature. However, when developmental processes go awry, then birth defects, cancer and other diseases can result. Our research is centered on understanding how development normally occurs in the hope of one day treating diseases that result from abnormalities in these processes. We focus largely on craniofacial and dental development, as malformations in these organs are among the most common congenital abnormalities and have profound impacts on the lives of patients and their families. We also study normal and perturbed development of the skeleton, taste papillae, external genitalia, gastrointestinal tract, and other organs, and we investigate how embryonic and adult stem cells self-renew and differentiate.
My goal is to investigate how neuronal-epithelial interactions control organogenesis and regeneration. My work primarily utilizes the mouse embryonic submandibular gland ex vivo model system to examine the role of the parasympathetic ganglion in epithelial branching morphogenesis and regeneration.
The submandibular gland has an autonomic ganglion located in and around the glandular epithelium from the earliest stages of development, and remains with the gland after dissection for ex vivo organ culture. This makes the salivary gland an exceptional model for understanding the influence of the peripheral nervous system on organogenesis and repair processes. During my post-doctorate I discovered that the parasympathetic ganglion plays a critical role in submandibular gland morphogenesis by maintaining keratin 5+ epithelial stem/progenitor cells through an acetylcholine /muscarinic/epidermal growth factor receptor pathway. In addition, I found this pathway maintains progenitor cells in the developing prostate and the adult submandibular gland. More recently I have also established that the neurotrophic factor neurturin secreted by the submandibular gland epithelium is required for parasympathetic ganglion function and survival, and increases organ regeneration after injury. Current projects examine 1) the regulation of stem cell factors by the nervous system during development and regeneration; 2) understanding how stem cells and the nerves are influenced by therapeutic radiation and disease; and 3) how neurotransmitters regulate epithelial architecture and stem cell movement during organogenesis. To investigate these processes we use a combination of genetic, high resolution microscopy and biochemical approaches with the aim of correlating our findings with human tissue.
Our focus has been on the cell biological processes that promote and maintain sensory signaling and neuronal plasticity throughout development. Neurons are the front-line of an organism’s response to its environment. Thus, understanding how their signaling components organize to perceive and transmit information both in response to novel and persistent cues is key to understanding behavior. We are testing the hypothesis that signaling pathways act via small RNAs to modify chromatin thereby allowing for experience-dependent changes in the output response. We utilize C. elegansfor our investigations because this nematode, with only 1,000 cells and 302 neurons exhibits robust behavioral plasticity and we can use cell biological, genetic, behavioral, physiological and molecular techniques to understand the molecular details that underlie experience driven changes in behavior. The molecular and cellular logic that underlies behavioral plasticity in C. elegans is likely to be utilized in the nervous system of higher organisms and humans and insight we gain from examining this nematode may inform both normal processes such as learning and memory as well as help us understand what goes awry in disease states such as addiction and perhaps attention deficit disorders. Our particular focus is on the olfactory sensory circuit of C. elegans.
Dr. Le’s research interest is to investigate the structures and functions of enamel extracellular matrix proteins in tooth formation, with particular emphasis on alternatively spliced amelogenins. Mutations in these enamel matrix proteins result in inherited enamel defects, called amelogenesis imperfecta. However, much is still unknown about the roles of these enamel proteins in amelogenesis.
His second clinical research project is to study the pulp revascularization of necrotic immature permanent teeth. The objective of this study is to evaluate a new clinical method for regenerating the functional development of incompletely developed permanent teeth with a diagnosis of pulpal necrosis, and to compare the clinical outcome measures to a current standard method of treatments such as calcium hydroxide or MTA apexification.
Our lab has focused on the roles of matrix proteins and proteinases in the development of tooth enamel and dental diseases for years. We are using biochemical and biophysical approaches to study enamel matrix proteins, enamel and dentin proteinases and their interactions. We are studying how the gene mutations results in the changes of protein functions and protein-protein interactions in diseases and development.
Dr. Marcucio's research program focuses on two basic science areas. First, using cutting-edge genomic technology, Dr. Marcucio is examining how the entire genome responds to orthopaedic trauma. This genome-mining approach is aimed at determining the global genome response during fracture repair and allows the possibility to generate improved, highly innovative therapies for people undergoing fracture repair. Second, Ralph is examining the role that the brain plays during normal development of the facial skeleton. Many facial birth defects have an underlying brain malformation, and the goal of the research is to generate novel therapeutic approaches that will allow correcting facial malformations prior to birth.
We study structure-mechanical property relationships of calcified tissues (bone, cementum, dentin, enamel). The main functions of these biological materials are mechanical, but much work is needed to understand how their unique and versatile properties are derived based on combinations of protein and mineral. We seek insight into biomineralization processes associated with these tissues during development, resulting from disease, or repair and regeneration from clinical treatments. We also focus on natural interfaces between various calcified tissues and artificial interfaces between the tissues and artificial, e.g., dental restorations, implants, bioactive substrates. We use a wide variety of approaches including atomic force microscopy (AFM); and AFM-based nano-indentation) as well as other complimentary methods including wet SEM and x-ray microanalysis, and participate in wide ranging collaborations in the Bay Area. This work helps define alteration in properties and structure with hydration state, mineral level, and variations induced by disease and physiological processes. This information is needed to develop a composite structural model of calcified tissues and can assist in the development of bio-inspired materials and tissue engineering.
Dr. Marshall, a 22-year veteran at UCSF, is the vice provost of academic affairs and director of the Office of Faculty Development and Advancement. She is also a professor of biomaterials and bioengineering in the Department of Preventive and Restorative Dental Sciences in the UCSF School of Dentistry. Beyond UCSF, she serves as a guest staff scientist at the Lawrence Berkeley National Laboratory, and is a former president of the International Association for Dental Research and a fellow of the Academy of Dental Materials. Marshall earned a bachelor of science degree and a PhD degree in materials science and engineering from Northwestern University.
Dr. Mertz is a dental sociologist, health services and dental policy researcher. Her work focuses on the role of the health professions within the changing health care system and the implications for access to high quality, affordable health care. The majority of her research has been focused on access to dental services and related professional and delivery system issues within dentistry, including trends in the dental and dental hygiene workforce and labor market issues such as shortages, role differentiation, diversity, demand and supply. Her recent research has focused on workforce innovations and care delivery system changes in dental care in relation to diversity, disparities, access to care, and oral health outcomes and quality improvement.
She is Principal Investigator on several recent projects; a national sample survey of Underrepresented Minority Dentists which will be the first ever documentation of the contributions of minority providers to minority oral health care; an evaluation of a dental post-baccalaureate program which documents the long term outcomes produced by dentists trained in this alternative pathway, and an analysis of the elimination of the adult dental benefit from the California Medicaid program which documents large changes in the safety net workforce resulting from this policy change. Research on the dental care delivery system and the dental workforce is rarely framed within sociological theory or practice. Past sociological studies of dentistry, while informative, are considerably out of date. The current dental care environment is on the verge of potentially rapid change; faced with ongoing access to care problems, increasing health disparities, advances in science and technology and changing economic and political conditions, the professions and policy-makers are actively searching out new solutions. Understanding these challenges and changes will require the use of a wide sociological lens; one that can fully account for the power of the professions and the agency of their members, but that can also account for trends in the organizational, environmental and social context.
Her research agenda is to advance the understanding of dental care delivery systems and professions in a way that will help policy makers, educators, and practitioners improve their ability to translate science into practice and address the oral health care needs of the public through affordable, high quality, accessible services.
Our orthodontic program works in collaboration with several programs including a long-term interaction with Dr. Koutaro Maki who Chairs the Showa University Department of Orthodontics in Japan. The Division of Orthodontics at UCSF has developed a three-dimensional volumetric imaging library since 2001 based on these collaborations and has recently acquired the third generation CBCT system to continue these studies of the human craniofacial region. We have developed a variety of joint projects that incorporate our orthodontic residents. The cone beam CT system at UCSF has now become the standard for clinical care in our Division of Orthodontics, and is rapidly becoming a standard for other advanced postgraduate programs at UCSF. Two of our orthodontic residents, whom I co-mentored, Dr. Chad Sears, and Dr. Eric Haney, won the Thomas M. Graber Research Award for Special Merit in 2007 from the American Association of Orthodontists. We are in the forefront of developing how CBCT can be used, and how craniofacial development can be followed with highly accurate and three-dimensional volumes that render the skeleton, the airway, and facial profile. We are working with several of our faculty to incorporate CBCT in the dental curriculum. Cone beam CT will become the standard for radiographic and 3-D analysis in dentistry in the next generation of dentists, and UCSF dental students and postgraduate students will be on the forefront.
My research program focuses on identifying and characterizing issues of disparities in access to oral health care in minority children and adolescents. Specifically, it focuses on disparities in access to orthodontic care in Latino children and adolescents.
Oral Squamous cell Carcinoma Project
Squamous cell carcinoma (SCC) represents approximately 96% of all oral cancers. The 5 year survival rate for this disease has not improved in over 60 years and remains at 50%. During oral cancer progression, the cells lose their polarity and become undifferentiated through the process of Epithelial to Mesenchymal Transition (EMT). It is at this time when αvβ6 integrin is first expressed. The β6 integrin is upregulated in several epithelial malignancies including oral cancer and is associated with increased EMT. avβ6 can bind fibronectin and the latency associated peptide-1 (LAP) of TGFβ1. Binding of avβ6 to LAP activates TGFβ1. The overexpression of avβ6 on tumors, particularly at the tumor-stromal interface, may reflect a unique mechanism for local activation of TGFβ1. Our recent work has shown that the mesenchymal properties of the tumor cells associated with the invasive oral SCC cells is regulated by the cytoplasmic tail of the β6 and the removal of the tail redifferentiates the cells into a more epithelial phenotype which is characterized by increased expression of E-cadherin and keratin.
Melanoma cell project
Mucocutaneous melanoma has an extremely poor prognosis due its highly aggressive behavior. The five-year survival rate is less than 10%. Our previous studies in melanoma demonstrate that upregulation of the αvβ3 integrin is required to maintain the invasive phenotype. Invasion requires a continued extension and retraction of the cell membrane that is mediated by the actin cytoskeleton. Cofilin, a 21kD protein, is responsible for both polymerization and depolymerization of actin. We are working on defining the mechanism underlying cofilin function. Our preliminary results indicate that αvβ3 integrin promotes invasion by suppressing the default RhoA/ROCK/LIMK1 pathway.
We are performing clinical studies to show preventive effects of new oral hygiene products, including new delivery systems for traditional caries prevention agents. We also research new agents for caries prevention. In the field of caries prevention we apply new lasers to render enamel caries resistant and use this new upcoming generation of lasers for micro-invasive dentistry. Laser applications in prosthodontics are also investigated
We have experience in research with newly developed light based diagnostic tools – for caries detection and for use in the periodontal area.
Dr. Schneider's current research program focuses on molecular and cellular mechanisms underlying development of the musculoskeletal system. He and his lab have been employing an avian chimeric transplantation system to exploit the divergent maturation rates and distinct species-specific anatomies of quail and duck. Specifically, his lab has been exchanging mesenchymal stem cells between quail and duck embryos, which challenges resultant chimeras to assimilate donor versus host-specific differences in growth and morphology. Using this approach, his lab has been identifying genes and signaling interactions that regulate the timing of musculoskeletal tissue differentiation, control size and shape, and which ultimately enable cartilage, bone, and muscle to achieve structural and functional integration. A goal of Dr. Schneider's research is to devise molecular-based therapies for inducing repair and regeneration of musculoskeletal tissues affected by congenital defects, disease, and trauma.
Dr. Shiboski is the principal investigator of the Oral HIV/AIDS Research Alliance (OHARA) UCSF site, which is the Epidemiology Unit of this multicenter grant and is part of the AIDS Clinical Trial Group Network (ACTG). She is currently involved with several OHARA research protocols that are being implemented in ACTG sites in the US, Africa, India, and Peru. Dr. Shiboski is also the lead Epidemiologist in the Sjögren’s Syndrome International Collaborative Clinical Alliance (SICCA), a project aimed both at establishing new classification criteria for Sjögren’s Syndrome and at developing a data and biospecimen repository for this disease.
Dr Tetsu has benefited from extensive training in cancer and molecular biology after a residency in general and abdominal surgery. Dr Tetsu receives his MD and his PhD in Japan and moved to the United States in 1997 for postdoctoral training with Dr Frank McCormick. Since then, Dr Tetsu has discovered that cyclin D1 is a b-catenin target gene (Nature 398, 1999) and that CDK2 kinase activity is dispensable in cancer cells (Cancer Cell 3, 2003). In addition, Dr Tetsu collaborated with his colleagues and identified causative genes in the MAPK signaling pathway in cardiofaciocutaneous syndrome (Science 311, 2006; Hum Mol Genet 17, 2008). Moreover, Dr Tetsu found that cyclin D1 degradation is mediated by phosphorylation at Thr286 through the MAPK signaling cascade and the FBXW8, which is an E3 ligase (PLoS One 1, 2007). Recently, Dr Tetsu is focusing his research interests in adenoid cystic carcinoma (ACC) of the salivary glands, and identified cross-contamination and misidentification of ACC cell lines (PLos One 4, 2009), and has discovered inactivation of c-Kit signaling in ACC tumors in collaboration with Dr Richard Jordan (Neoplasia 12, 2010).
Dr. Wittmann's laboratory focuses on the function and spatiotemporal regulation of the microtubule cytoskeleton during complex cell behaviors. Microtubules are polymers that frequently switch between polymerization and depolymerization. These non-equilibrium dynamics may allow microtubule ends to explore the cytoplasm to interact with specific intracellular targets. We are interested in a fascinating group of proteins that are defined by their dynamic localization to growing microtubule ends in cells. The functions of these +TIPs are not well understood. In addition, it is quite mysterious how +TIPs recognize growing microtubule ends, and microtubule association of certain +TIPs is spatiotemporally regulated in cells. We use biochemical and cell biological techniques in combination with live cell confocal microscopy to examine how these and other cytoskeletal proteins determine cell behavior in different experimental model systems. This includes planar polarized keratinocytes that directionally migrate at the edge of epithelial cell sheets, apical-basal polarized epithelial cells in a three-dimensional extracellular matrix, and endothelial cells that establish planar polarity in response to fluid shear stress.
I study the evolution and development of the human face, and utilize two complementary approaches in my research. In the first I take a "gene up" approach to understand how variation in genetic and molecular factors contribute to differences in early facial morphogenesis. This kind of research has clinical implications, since disruptions to normal developmental events often lead to craniofacial birth defects, and these often express a range of severity that has been previously difficult to predict and understand. In the second, I take a "phenotype down" approach, analyzing variation in the faces of children and adults to understand how growth impacts shape, and the genetic factors that contribute to variation among individuals. The ultimate goal of this research is to better predict individual facial shape and growth, and apply this information in clinical contexts to better "personalize" individual prognoses and treatment plans.
Dr. Zhan’s primary research interest is to understand microbiological aspects of dental caries and identify protocols that will lead to prevention or elimination of dental caries in children. One of her research focus is on virulence factors of mutans streptococci and other caries-causing bacteria that are related to their transmission or initiation of dental decay. The overall goal of these studies is to identify specific genes in MS that are related to development of dental caries in children and investigate whether these genes can be used to screen children with high risk for antimicrobial treatment and also to develop targeted antimicrobial agent for caries prevention in children. The other aspect of her research is focused on seeking clinical regimens in caries prevention. She has conducted randomized clinical trails to identify effective practical antimicrobial regimens, such as povidone iodine and xylitol products, which may alter caries-causing bacteria challenge and prevent new caries in children.
The third aspect oh her research is to study and develop an effective and practical Caries Management by Risk Assessment protocol (CAMBRA) for children.
She is also interested in global oral health projects and recently engaged study on investigating the feasibility and efficacy of incorporating oral health education and fluoride varnish program through pediatric immunization clinic in Roatan, Honduras with a joint effort of a multidisciplinary team from UCSF and UC Berkley.
Oral epithelium derived dental epithelial cells go through multiple developmental stages to differentiate into ameloblasts, which are responsible for enamel formation. Enamel is the hardest mineralized tissue in our body, and the main line of defense for dental decay. Enamel cannot regenerate itself since ameloblasts commit apoptosis when teeth erupt. My research has been focusing on bioengineering functional human ameloblasts from accessible human non-dental epithelial cells, which aims to fill the gap of lack of a cell source for enamel tissue bioengineering and eventually tooth repairing. We are aiming to use transcription factors that we have identified to reprogram adult dental mesenchyme and enhance its instructive potential in driving the differentiation of recombined non-dental epithelial cells. In another parallel effort, we are using transcription regulators that are critical for enamel formation to directly transdifferentiate human non-dental epithelial cells.