Abstract

Parathyroid hormone-related protein (PTHrP) was discovered through its role in causing humoral hypercalcemia of malignancy (HHM). It is now clear that PTHrP not only is the cause of HHM, but also plays critical roles in skeletal development. Moreover, PTHrP is produced by almost every tissue in the body and acts as a regulator of: a) transepithelial calcium transport; b) smooth muscle tone; and, c) cellular growth, differentiation, apoptosis and organogenesis. The original version of this proposal focused on identifying the function of PTHrP in the pancreatic beta cell. To approach this question, we developed transgenic mice which overexpress PTHrP within the pancreatic beta cell using the rat insulin-II promoter (RIP). The studies performed to date indicate that RIP-PTHrP mice develop striking islet hyperplasia which results in hyperinsulinemia, and hypoglycemia. This is the only transgenic model of islet hyperplasia and hypoglycemia The mechanisms responsible for the increase in islet mass and function, however, are unclear: there are no changes in the rate of apoptosis nor of proliferation in RIP-PTHrP islets. In addition, while these studies demonstrate the consequences of targeted overexpression of PTHrP within the islet, they do not reveal whether PTHrP plays a normal role in the regulation of islet mass. The current proposal represents a natural extension of these studies. It has two Aims: 1. To Further Define the Mechanism by which PTHrP Increases Islet Mass. 2. To Determine Whether PTHrP Plays a Role in Normal Islet Physiology. These studies should more clearly define the role of PTHrP within the islet and should help to clarify whether PTHrP might prove of value in the treatment of diabetes. Most importantly, these studies should broaden the understanding of the mechanisms of action of PTHrP in the large range of normal tissues (parathyroid glands, the epidermis, the mammary gland, and the skeleton) which produce this ubiquitous paracrine/autocrine/intracrine factor.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047168-08
Application #
6476196
Study Section
General Medicine B Study Section (GMB)
Program Officer
Sato, Sheryl M
Project Start
1995-02-15
Project End
2002-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
8
Fiscal Year
2002
Total Cost
$269,961
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Fiaschi-Taesch, Nathalie M; Santos, Soledad; Reddy, Vasumathi et al. (2004) Prevention of acute ischemic renal failure by targeted delivery of growth factors to the proximal tubule in transgenic mice: the efficacy of parathyroid hormone-related protein and hepatocyte growth factor. J Am Soc Nephrol 15:112-25
Garcia-Ocana, Adolfo; Takane, Karen K; Reddy, Vasumathi T et al. (2003) Adenovirus-mediated hepatocyte growth factor expression in mouse islets improves pancreatic islet transplant performance and reduces beta cell death. J Biol Chem 278:343-51
Siddique, Aleem; Malo, Madhu S; Ocuin, Lee M et al. (2003) Convergence of the thyroid hormone and gut-enriched Kruppel-like factor pathways in the context of enterocyte differentiation. J Gastrointest Surg 7:1053-61; discussion 1061
Cebrian, Ana; Garcia-Ocana, Adolfo; Takane, Karen K et al. (2002) Overexpression of parathyroid hormone-related protein inhibits pancreatic beta-cell death in vivo and in vitro. Diabetes 51:3003-13
Garcia-Ocana, A; Vasavada, R C; Cebrian, A et al. (2001) Transgenic overexpression of hepatocyte growth factor in the beta-cell markedly improves islet function and islet transplant outcomes in mice. Diabetes 50:2752-62
Garcia-Ocana, A; Vasavada, R C; Takane, K K et al. (2001) Using beta-cell growth factors to enhance human pancreatic Islet transplantation. J Clin Endocrinol Metab 86:984-8
Luparello, C; Romanotto, R; Tipa, A et al. (2001) Midregion parathyroid hormone-related protein inhibits growth and invasion in vitro and tumorigenesis in vivo of human breast cancer cells. J Bone Miner Res 16:2173-81
Vasavada, R C; Garcia-Ocana, A; Zawalich, W S et al. (2000) Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia. J Biol Chem 275:15399-406
Garcia-Ocana, A; Takane, K K; Syed, M A et al. (2000) Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia. J Biol Chem 275:1226-32
Porter, S E; Sorenson, R L; Dann, P et al. (1998) Progressive pancreatic islet hyperplasia in the islet-targeted, parathyroid hormone-related protein-overexpressing mouse. Endocrinology 139:3743-51

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