ISLET GROWTH FACTORS--TRANSGENIC AND VIRAL MODELING

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (taken from the application) We have previously described the consequences of targeted over-expression of parathyroid hormone-related protein (PTHrP) in the pancreatic islet of transgenic mice using the rat insulin-II (RIP) promoter. These observations have focused the applicant's attention on transgenic approaches to defining the factors to the islet use using viral gene delivery strategies. With this background, we have recently prepared two additional lines of RIP-promoter targeted transgenic mice. One, the RIP- mPL-1 mouse, takes advantage of the observation that murine placental lactogen-1 (mPL-1) appears to participate in islet mass augmentation during pregnancy, and is able to increase islet proliferation rates in vitro. The second, the RIP-HGH mouse, starts with the premise that hepatocyte growth factor (HGF) appears to play a role in fetal islet development, and is able to stimulate islet proliferation in vitro. The RIP-HGF founders have very recently been prepared and can transmit the transgene, but have not yet been further characterized. The RIP-mPL-1 mice have been preliminary characterized, and are hypoglycemic, have an increase in islet mass, and an increase in islet proliferation rates. This proposal has three Specific Aims: 1. To further characterize the consequences of targeted over-expression of mPL-1 in the islet of the RIP-mPL-1 mouse. 2. To define the consequences of targeted over-expression of HGF in the islet in the RIP-HGF mouse. 3. To explore the therapeutic potential for viral gene delivery of PTHrP, mPL-1, and HGF in the pancreatic islet.