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.
The Barber Lab uses genetic and biochemical approaches to study the signal transduction pathways used by hormone and growth factor receptors in regulating cell growth. Their recent focus is on receptor regulation of the GTPase family of proteins that control the organization of the actin cytoskeleton. Dynamic changes in the actin cytoskeleton play a critical role in cell growth and differentiation, and they have determined that these dynamic changes are regulated by a complex interplay between adhesion molecules of the integrin receptor family, members of the Rho family of GTPases, and plasma membrane ion exchangers. Most interesting is the novel observation that the link between adhesion receptors and cytoskeletal organization requires selective members of the family of plasma membrane Na-H ion exchangers. They found that Na-H exchangers are structurally linked to the actin cytoskeleton through their direct association with ERM proteins of the protein 4.1 superfamily of actin-binding proteins. Hence, plasma membrane ion exchangers can link the actin network to the plasma membrane and thereby convey input from adhesion molecules and GTPase signaling networks to the output of cytoskeletal reorganization. The functional significance of this interplay between integrin receptors, Rho family GTPases, and plasma membrane ion exchangers in cell contractility, migration, and proliferation is currently being investigated.
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 .
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.
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.
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 Featherston 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.
Tumor cells are driven to proliferate, alter their metabolism, and deregulate cell death pathways by oncogene over-expression or the loss of tumor-suppressor genes. We seek to understand how oncogenes alter these pathways using cell-based and transgenic animal models. We are especially interested in how the prototypical oncogene Myc acts in diverse tumor types, including amongst the most aggressive breast and liver cancers and lymphomas. Myc has also been postulated to drive a 'stem cell like' gene expression pattern which may regulate tumor stem cell function. We seek to elucidate the genes and pathways that are indispensable for Myc function, and thus uncover potential 'achilles heels' of tumor cells. Our ultimate goal is to translate our basic discoveries to novel cancer therapeutics.
2. Regulation of Oncogenes and Tumor Suppressor Genes by miRNAs.
3. Metabolic Adaptations in Cancer.
"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 twenty-eight 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. Our contributions are indicated in my CV but I would mention that 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 for the last eight years. 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 in the planning of the emerging UC Systemwide School of Global Health.
As Director of the UCSF AIDS Research Institute for the past eight years, 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. As Associate Dean for Global Oral Health 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.
My research interests are in two different, but overlapping areas: 1) Epigenetic factors and form – function relationships; 2) Regeneration of soft-hard tissue attachment.
Functional efficiency of most organs is broadly governed by two factors; genetic and epigenetic. In my laboratory we are currently studying the effect of two epigenetic factors: load and disease; and load plus disease on the bone-ligament-tooth complex using in vivo models. Furthermore, the observed load-based nanoscale events are mimicked by programming them as functional cues on synthetic substrates to promote tissue specific cell differentiation and regeneration for soft-hard tissue functional attachment.
1) Epigenetic factors influence on form-function relationship The bone-ligament-tooth complex is an excellent bioengineered system in which several natural interfaces between soft-hard or hard-hard tissues provide biomechanical efficiency of the fibrous joint. However, functional efficiency can be impaired if any one of the interfaces and/or tissues adapt to epigenetic factors: load and disease. In both diseased and/or load-based organs, resorption or formation related biomineralization events affect the interfaces. A systematic approach to investigate mineral resorption and formation related phenomena involves harnessing principles of mechanics, materials science, and mechanobiology at organ, tissue and cell-levels in the bone-tooth fibrous joint. Models include ligature induced periodontitis to investigate bacterial induced mineral formation and resorption, and functional load modulation by food consistency and/or imposition of unidirectional vectors to investigate force (magnitude and direction of load) induced mineral formation and resorption. This excellent model i.e. the bone-ligament-tooth complex can elucidate a wide spectrum of clinical scenarios, from bony spurs related to enthesopathies to tissue regeneration related to distraction osteogenesis in both musculoskeletal, and oral and craniofacial systems.
2) Regeneration of soft-hard tissue attachment The soft-hard tissue interfaces in the bone-ligament-tooth complex parallel several other similar interfaces in the musculoskeletal system including tendon-bone and ligament-bone interfaces. Challenges to date in oral and musculoskeletal systems include “functional regeneration” of “soft- and hard-tissue interfaces” that are seminal to the load-bearing nature of fibrous and diarthroidal joints. Parameters investigated under item 1 are programmed as “functional cues” on synthetic substrates to promote tissue regeneration/attachment specific to soft-hard tissue interfaces. Regeneration events include tissue-specific cell differentiation and basic constituents i.e. collagen, noncollagenous proteins, and apatite formation necessary to provide functional integrity for a load bearing interface.
The impending challenges in advancement of health care can be best addressed when fundamental science is synchronized with collaborations across several disciplines and clinical needs. Hence, the research team consists of scientists/clinicians within the Bay Area; Stanford Synchrotron Radiation Lightsource (SSRL), Stanford Linear Accelerator Center, and the Molecular Foundry, Lawrence Berkeley National Laboratory (LBL). Several interdisciplinary methods are implemented routinely to investigate the aforementioned research topics. These include macroscale in situ loading devices coupled to high resolution X-ray computed tomography, high resolution spectroscopy techniques for early and late stage chemical markers, micro- and nano-indentation to identify tissue differences and/or tissue heterogeneity through site-specificity, immunohistochemistry, fluorescence microscopy, dynamic histomorphometry and in situ hybridization. Other techniques include high resolution microscopy using atomic force, transmission X-ray, scanning electron microscopy techniques for micro and nano-scale analysis under dry and wet conditions. Extension of laboratory facilities within the Division of Biomaterials and Bioengineering is made possible through user proposals at the Molecular Foundry of LBL, and SSRL.
Edward Hsiao, MD, PhD, is an endocrinologist at the University of California, San Francisco.
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
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.
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.
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. elegans for 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.
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.
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.
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.