Glucose hofrieostasis is prirharlly maintained by the intricate bsilance of the glucoregiilatory, pancreatic hormones insulin and glucagon. Type 1 diabetes meljitus resijlts fironn the autoimmune destruction of pancreatic beta cells vt/h|ch produce insulin. Currently, the onjy available cure for type 1 diabeties is pancreatic or iislet transplantation, A prihriary linnitatJbn of theise bona fide cures is the limited availability of pancreataand paricreatic islets from cadaver donors. Because of thjs bottleneck, much work has been perfonned with the goal of finding an aiternative source of insulin-producing cells as well as establishing riiethpds to stimulate proliferation bf islets harvissted for transplantation. The current application addresses the critical need to establish methods to increase pancreatic islet mass. If successful, nfiore patients with type 1 diabetes will benefit from islet transplantation and be free from this serious disease. We have recently discovered that the pf-btease-reslstant peptide trefoil factor 3 (TFF3) is a jgrpwth factor for pancreatic islets. Since the discovery of TFFS's ability to increase cell proliferation of pancreatic beta cells, vt/e have begun to uncover the signaling pathways that lead tO: this beneficial effect. However, much work remains to fully characterize these pathways and to perhaps reveal other pathways that can be exploited in order tb Increase pancreatic beta cell tmiass. Further, it is equallylmportantto continue to identify novel factors that have the abiJify to increase beta cell mass. In pursuit of these goals.the following specific aims are proposed: 1) to determine the role of EGFlreceptor signaling on TFF-3 induced beta cell proliferation, 2) to determine the ro e of Gene 33/Mig-6/RALT in mbdulatlng EGF receptcr signaling and beta cell proliferation, and 3) to identify noverfactors that regulate pancreatic beta cell mass. The results of this work might increase the therapeutic efficacy of islettrahsplant^tlpn.:

Public Health Relevance

Because to the limited avallabilty of pancreatic islets from cadaver donors, islet transplantation has limited utility as a cure for type i diabetes. This work addresses the Critical nised to expand the beta cell mass in an effort to increase the number of patients with type 1 diabetes that can afford the benefit of islet transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
3R00DK078732-04S1
Application #
8139438
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sato, Sheryl M
Project Start
2007-09-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$2,310
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Chen, Yi-Chun; Colvin, E Scott; Griffin, Katherine E et al. (2014) Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes. Diabetologia 57:2066-75
Hernandez, Angelina M; Colvin, E Scott; Chen, Yi-Chun et al. (2013) Upregulation of p21 activates the intrinsic apoptotic pathway in ?-cells. Am J Physiol Endocrinol Metab 304:E1281-90
Colvin, E Scott; Ma, Hong-Yun; Chen, Yi-Chun et al. (2013) Glucocorticoid-induced suppression of ?-cell proliferation is mediated by Mig6. Endocrinology 154:1039-46
Chen, Yi-Chun; Colvin, E Scott; Maier, Bernhard F et al. (2013) Mitogen-inducible gene 6 triggers apoptosis and exacerbates ER stress-induced ?-cell death. Mol Endocrinol 27:162-71
Fueger, Patrick T; Hernandez, Angelina M; Chen, Yi-Chun et al. (2012) Assessing replication and beta cell function in adenovirally-transduced isolated rodent islets. J Vis Exp :
Kelly, Patrick; Bailey, Candice L; Fueger, Patrick T et al. (2010) Rap1 promotes multiple pancreatic islet cell functions and signals through mammalian target of rapamycin complex 1 to enhance proliferation. J Biol Chem 285:15777-85