Dr. Bass has had extensive training in metabolism related biomedical research beginning with work as an M.D., Ph.D. student at the Medical College of Pennsylvania under the direction of Drs. Julian Marsh and Edward Fisher. There the role of tissue macrophages in the secretion of apolipoprotein E and cholesterol uptake was investigated. Subsequently, the P.I. completed residency in Internal Medicine and a Fellowship in Endocrinology under the Clinical Investigator Pathway of the American Board of Internal Medicine. For the past 3 years the P.I. has worked with Drs. Donald Steiner and Graeme Bell at the University of Chicago where he investigated the biosynthesis and structure of the insulin receptor. This work provided the foundation for the present application. The insulin receptor is a large and complex glycoprotein that undergoes extensive posttranslational modification important in its translocation and expression. Yet, the molecular details underlying the biosynthetic pathway remain inadequately understood. Recently, Dr. Bass has shown that nascent insulin receptors associate with three resident endoplasmic reticulum (ER) molecular chaperones, calnexin (Cnx), calreticulin (Crt) and binding protein (BiP) and blocking these interactions reduces the cell surface expression of the receptor.
The aim of this project is to dissect the molecular mechanisms by which these chaperones effect insulin receptor biogenesis. The approach is to use pulse-chase labeling, coimmunoprecipitation with antibodies to the receptor and to the three chaperones, in combination with pharmacologic and genetic methods to disrupt receptor-chaperone interactions. The experiments will involve site-directed mutagenesis, transfections, and analytic techniques such as sucrose velocity sedimentation and confocal microscopy. These studies will illuminate the quality control mechanisms that regulate delivery of functional receptors to the cell surface. The University of Chicago provides an outstanding environment for basic diabetes-related research. The Department of Medicine has long fostered the careers of young scientists. The ability of the P.I. to interact with the sponsor, Dr. Steiner, in addition to Drs. Graeme Bell, Susan Lindquist and other excellent scientists at the University of Chicago will promote his continued development as an independent researcher.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002675-04
Application #
6380117
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
1999-09-15
Project End
2004-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
4
Fiscal Year
2001
Total Cost
$118,800
Indirect Cost
Name
Evanston Hospital
Department
Type
DUNS #
City
Evanston
State
IL
Country
United States
Zip Code
60201
Turek, Fred W; Joshu, Corinne; Kohsaka, Akira et al. (2005) Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308:1043-5
Bass, J; Turck, C; Rouard, M et al. (2000) Furin-mediated processing in the early secretory pathway: sequential cleavage and degradation of misfolded insulin receptors. Proc Natl Acad Sci U S A 97:11905-9
Dayal, B; Bhojawala, J; Rapole, K R et al. (1996) Chemical synthesis, structural analysis, and decomposition of N-nitroso bile acid conjugates. Bioorg Med Chem 4:885-90