Professor of Medicine
Professor of Cell Biology and Physiology
Research interests center on the genetic and physiological bases of diabetes. In particular, current studies include the following:
1) Control of Insulin Biosynthesis: The study of glucose-regulated insulin biosynthesis in experimental animals, and evaluation of the genes which mediate these response in man. The hypothesis to be tested is that defects in these regulatory genes are responsible for at least some of the inherited susceptibility to Type II Diabetes Mellitus.
2) Functional Genomics of the Developing Endocrine Pancreas: The identification and characterization of genes involved in pancreatic development and function. This includes genes implicated in generating islets and the pancreas as well as genes defining the physiological function and dysfunction leading to the diseased states in type 1 and type 2 diabetes. We propose to construct comprehensive cDNA libraries from both humans and mice. These libraries will be used to prepare cDNA chips (microarrays) that will serve as quantitative and standardized assays for gene activity.
3) Metabolic Basis of NIDDM: A Sib-Pair Analysis: A database collected on 400 affected Ashkenazi Jewish sib pairs and 200 spouse controls will be established, including family history and country of origin, date of birth, sex, height, weight, blood pressure, waist/hips ratio, age of diagnosis, treatment, presence of complications and presence of hypertension or dyslipidemia; Genetic markers and multiplex PCR techniques will be developed for subsequent genotyping of the sib-pair DNA; 3) A whole genome search will be undertaken using SSRPs and methodology developed under #2; 4) Data analysis will be conducted using the nonparametric identity by state (IBS) analysis on all affected sib pairs. In the pending proposal three specific aims are proposed. 1) We will complete linkage analysis in families, by genotyping additional individuals with more dense markers across the 6 regions. 2) Based on the linkage results, one chromosomal region will be fine mapped by linkage disequilibrium analysis in unrelated individuals. This will require constructing a physical map of the region, and identification of as many as 300 single nucleotide polymorphisms at 30-kb intervals or less. 3) Positional cloning of the gene from the region narrowed to perhaps <1 Mb by linkage disequilibrium. Candidate genes will be identified within the region by completion of genomic sequencing, followed by mutational analyses.
4) Mechanisms for Premature Death of Islet _-Cells in a Form of Juvenile-Onset Diabetes Mellitus: To create a mouse model of Wolfram Syndrome (WFS) to test the hypothesis that the WFS gene, WFS1, encodes an islet protein that controls a novel cell survival pathway.
Awards and Honors
1965: Borden Prize for Medical School Research; Alpha Omega Alpha
1972-77: Howard Hughes Medical Investigator
1975-77: St. Louis Diabetic Children’s Welfare Association Award
1977-82: Research Career Development Award-NIH
1986-94 NIH MERIT (Method to Extend Research in Time) Status Award
1995: David Rumbough Award for Excellence in Research (Juvenile Diabetes Foundation International)
1996: Barbara Davis Distinguished Research Award
1998-06: NIH MERIT (Method to Extend Research in Time) Status Award