New
Grants Awarded (2006-2007)
James E. Melvin, D.D.S., Ph.D.
Director, Center for Oral Biology
Professor of Pharmacology & Physiology in the Center for Oral Biology
Training Program in Oral Science
NIH 5T32DE07202
The Center for Oral Biology in the Aab Institute of Biomedical Sciences, in collaboration with the Departments of Pharmacology & Physiology, Microbiology & Immunology, Biomedical Genetics, Dentistry, Medicine and Dermatology, has been awarded $4M in funding by NIDCR/NIH to continue support for their T32 grant “Training Program in Oral Science.” A greater number of highly skilled, interactive clinician-scientists (DDS/DMD, MD, and PhD) with diverse expertise and who can effectively respond to the growing opportunities in dental, oral and craniofacial research must be generated for society to take advantage of the rapid and dramatic advances being made in the biomedical sciences.
Thus, the overall goal of the Training Program in Oral Science is to provide enhanced training opportunities for oral biologists and dentist-scientists that will enable them to pursue research careers in dentistry and medicine at academic, federal and industrial organizations. Cross-disciplinary training will focus on the fields of oral infectious diseases and the cellular, developmental and molecular biology of craniofacial structures with an emphasis on understanding the basic mechanisms that underlie the clinical manifestations of oral disease. The proposed curriculum will focus on the integration of basic science research and clinical practice. The Training Program focuses on the recruitment of dentists who wish to pursue a PhD and dentist-PhDs who want to engage in post-doctoral level training. A major component of the program is committed to the recruitment of dental students into a joint DMD-DDS/PhD program (DSTP). These are students who wish to coordinate their clinical training with PhD research studies. This novel program partners dental schools with excellent clinical programs, but with no PhD level training (University of Puerto Rico and Marquette University), with the highly regarded PhD programs at the research-intensive University of Rochester School of Medicine & Dentistry. We will also recruit PhDs and baccalaureate degree-holders pursuing a PhD. In this manner, PhD level scientists can be exposed and ultimately recruited to the field of Oral Science.
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Mechanisms of Anion Transport Proteins in Salivary Cells
NIH
2 R01 DE09692
4/1/06-3/31/11
The major goals of this project are to 1) characterize clones from rat salivary gland cDNA libraries, 2) determine the kinetic properties of chloride channel proteins in salivary acinar cells, 3) examine the regulation of chloride conductance, and 4) assess the functional significance of chloride channels in salivary acinar cells.
Wei
Hsu, Ph.D.
Associate Professor of Biomedical Genetics
in the Center for Oral Biology
Mammary Stem Cells in Development and Cancer
DOD Breast Cancer Research Program BC060349
5/14/07-6/13/10
The primary focus of this proposal is to explore the role of newly identified mammary stem cells in mammary development and tumorigenesis.
Genetic Regulatory Network in Craniofacial Development
NIH R01 DE015654
7/1/06-5/31/11
The goal of this proposal is to delineate the genetic regulatory circuitry
in craniofacial morphogenesis. We study the genetic control of developmental
signals regulating calvarial osteoblast development in cranial skeletogenesis
and craniosynostosis.
Catherine
Ovitt, Ph.D.
Assistant Professor of Biomedical Genetics
in the Center for Oral Biology
Salivary Gland Development and Regeneration
NIH R21 DE017386
4/1/06-3/31/08
Studies focus on: 1) To identify a subpopulation of salivary gland
cells which includes progenitor cells capable of reconstituting multiple salivary
cell types. These experiments will test the hypothesis that duct cells include
multipotent precursor cells that are suitable for repopulation of atrophic
salivary glands and will establish optimal conditions for their cultivation.
2) Introduce cultured precursor cells into a damaged salivary gland, and establish
an assay for the correct functioning of these cells.
Robert G.
Quivey, Jr., Ph.D.
Professor of Microbiology & Immunology
in the Center for Oral Biology
Fitness Profling of the Streptococcus mutans genome
NIH R01DE017425-01A1
6/1/07-5/31/12
The major goals of the proposed project are the following: Specific Aim 1a. High throughput methods will be tailored to reproducibly delete individual genes in the entire S. mutans genome. Each deletion will be marked by the presence of two unique DNA sequences (18-20 bp) such that abundance of each particular mutant strain in a population of mutants and wild type can be scored using these “bar codes.” Specific Aim 1b. A genomic set of marked deletions will be constructed, resulting in a library of S. mutans strains bearing knockouts of all non-essential genes. Methods to analyze gene function by fitness profiling will be used to determine a function for each gene in S. mutans. Specific Aim 2. To find genes that may affect growth in the oral cavity, we will test mutant strains for their ability to grow, in vitro, in acidic conditions. Then, we will use the knockout library in fitness profiling experiments under defined conditions, which will include the following: 1) co-culture of the library of mutant strains growing in acidic environments, including planktonic and biofilm cultures; and, 2) a mouse infection model, in which the mice are fed a highly cariogenic diet. These experiments will be done as screens for candidate strains to be examined individually in the mouse caries model. Specific Aim 3. We will also examine the ability of the library of mutant strains to grow in the presence of additional species of oral microbes, with the aim of identifying those genes in S. mutans that contribute to its ability to out-compete other oral organisms.
Low pH-mediated membrane biosynthesis in S. mutans
NIH R01DE017157
7/1/06-5/31/11
Specific aims include: 1) we will complete our biochemical
characterization of pH-dependent changes in membranes, with
the goal of measuring changes in phospholipids and branched
chain fatty acids; 2) we will use biochemical and molecular
tools to determine the mechanism of genetic regulation of fab
genes and the role of fabR in regulating the fab gene cluster;
3) we will use biochemical and genetic tools to elucidate the
relationship of FabM and FabK to membrane composition; 4) we
will determine how pH-dependent changes in S. mutans membranes
relate to fluidity; 5) finally, we will determine how S. mutans
uses its fab genes to respond to membrane disrupting agents
such as cerulenin and tt-farnesol.
Collaborative Awards with COB Faculty
Ted Begenisich, Ph.D.
Professor of Pharmacology and Physiology; Professor in the Center for Oral Biology
The Physiological Roles of K Channels in Fluid Secretion
NIDCR R01 DE016960-01A1
3/1/06-2/28/11
The goal of the study is to understand the physiological roles of the Ca2+-activated K channels that are expressed in salivary glands. This will be accomplished with molecular, genetic, biochemical, optical, and electrophysiological approaches to test for their co-localization and to understand their Ca2+ sensitivities and the mechanism of their interaction. The studies also include examining physiological fluid secretion in K channel deficient mice and testing the applicability of the results with the mouse system to human parotid function.
(Melvin- Co-Investigator)
Ignacio Sanz, M.D.
Professor of Medicine, and of Microbiology & Immunology
Identification of Biomarkers in Sjorgren's Syndrome
NIDCR
R01 DE017585-01
8/1/06-7/31/11
In Aim 1, we will identify salivary proteins associated with SS. In Aim 2, we will identify an autoantibody signature characteristic of SS. In Aim 3, we will identify and validate biomarkers for the diagnosis and evaluation of SS. Taken together, the results of these studies will address gaps in our understanding of the correlation between blood and saliva Ss-specific biomarkers, salivary gland function, and disease progression, and will allow us to better understand the pathogenic processes resulting in the salivary infiltration by autoimmune memory Bcells and to develop a practical approach for the measurement of autoantibodies as SS biomarkers in the clinic.
(Melvin- Co-Investigator)
Robert Marquis, Ph.D.
Professor of Microbiology & Immunology and of Oral Biology
Oxidative Stress in Oral Streptocci
5 RO1 DE13683-06A1
7/1/06-6/30/11
This project is devoted to understanding the mechanisms by which the oral pathogen, Streptococcus mutans, protects itself from oxidative damage caused by its own metabolism, the metabolic products of other oral organisms; or potentially, oxidative chemicals in current use as therapeutic agents. The goal of the program is to identify additional targets for therapeutic intervention of the caries process.
(Quivey - Co-Investigator)
