The overall goal of this program project is to characterize the cellular and molecular basis of the immune pathogenesis of insulin-dependent diabetes mellitus (IDDM). The information obtained will be utilized to design a specific immune intervention strategy to prevent or treat IDDM. The program project involves a collaborative interaction between four departments. The grant is organized into four individual projects supported by three cores. The expertise of the project leaders bridge the disciplines of immunology, biochemistry, genetics, and pathology. The will use a wide range of techniques to characterize the immunologic and molecular perturbations, leading to the selective destruction of pancreatic beta cells. Project 1 will focus on the feasibility of islet- directed gene transfer to express several well characterized chemokines within islet allografts to promote local immunomodulation. Project 2 will investigate the intra-islet T-cell immunoregulatory events and the delineation of several putative autoimmune diabetes of NOD mice. Novel immune intervention strategies will be applied to treatment of diabetic NOD mice with islet transplantation. Project 3 will focus on the physical and metabolic characteristics of islet tissue to explore the technology of genetic engineering for modification of islet tissue prior to transplantation. Project 4 will focus efforts on characterizing the sphingomyelinase/ceramide and phospholipase A2 signal transduction pathways in mediating the effect of cytokine in the beta cell destruction. Core units for project administration, islet isolation, and vector preparation will provide necessary coordination and infrastructure for the program project. Collectively, this program project is an integrated and focused multidisciplinary effort to list the mechanisms that lead to the destruction of pancreatic beta cells in diabetes mellitus. The proposed studies are designed to elucidate the pathophysiology of IDDM and to utilize modern transplantation and molecular techniques to improve the treatment of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK049814-05
Application #
2905754
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Abraham, Kristin M
Project Start
1995-06-10
Project End
2000-05-31
Budget Start
1999-07-15
Budget End
2000-05-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sun, Zheng; Miller, Russell A; Patel, Rajesh T et al. (2012) Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med 18:934-42
Zhao, G; Moore, D J; Lee, K M et al. (2010) An unexpected counter-regulatory role of IL-10 in B-lymphocyte-mediated transplantation tolerance. Am J Transplant 10:796-801
Yang, Jichun; Wang, Chunjiong; Li, Jing et al. (2009) PANDER binds to the liver cell membrane and inhibits insulin signaling in HepG2 cells. FEBS Lett 583:3009-15
Huang, Xiaolun; Moore, Daniel J; Mohiuddin, Mohammad et al. (2008) Inhibition of ICAM-1/LFA-1 interactions prevents B-cell-dependent anti-CD45RB-induced transplantation tolerance. Transplantation 85:675-80
Noorchashm, Hooman; Reed, Amy J; Rostami, Susan Y et al. (2006) B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection. J Immunol 177:7715-22
Quinn 3rd, William J; Noorchashm, Negin; Crowley, Jenni E et al. (2006) Cutting edge: impaired transitional B cell production and selection in the nonobese diabetic mouse. J Immunol 176:7159-64
Yang, Jichun; Wong, Ryan K; Park, MieJung et al. (2006) Leucine regulation of glucokinase and ATP synthase sensitizes glucose-induced insulin secretion in pancreatic beta-cells. Diabetes 55:193-201
Burkhardt, Brant R; Greene, Scott R; White, Peter et al. (2006) PANDER-induced cell-death genetic networks in islets reveal central role for caspase-3 and cyclin-dependent kinase inhibitor 1A (p21). Gene 369:134-41
Yang, Jichun; Gao, Zhiyong; Robert, Claudia E et al. (2005) Structure-function studies of PANDER, an islet specific cytokine inducing cell death of insulin-secreting beta cells. Biochemistry 44:11342-52
Reed, Amy J; Zarrabi, Yasaman; Perate, Alison L et al. (2005) The frequency of double-positive thymocytes expressing an alphabeta TCR clonotype regulates peripheral CD4 T cell compartment homeostasis. Immunology 116:400-7

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