Inadequate ?-cell mass is common to both type 1 and type 2 diabetes. Our long-term research goal is to understand the signals that influence ?-cell growth, as a step towards regeneration of ?-cell mass in diabetes patients. Surprisingly little is known about how ?-cell growth is regulated, and few mitogenic signals have been demonstrated to influence ?-cell mass. Bone Morphogenic Proteins (BMPs) are attractive candidate mitogenic signals in adult ?-cells because of their roles in many embryonic tissues. There is no published evidence that BMPs influence adult ?-cell growth. But, a large number of in vitro studies indicate that BMPs influence embryonic ?-cell development. We will use inducible tissue specific gene deletion in mice to test the hypothesis that BMP signals regulate adult ?-cell growth. The rationale for our studies is strengthened by our preliminary studies: Systemic BMP4 treatment stimulates ?-cell proliferation in vivo, and acute Bmpr1a gene deletion severely reduces adult ?-cell proliferation. Hence, the following Specific Aims: 1. Test the hypothesis that Bmpr1a signals regulate adult ?-cell growth. 2. Test the hypothesis that Bmpr1b signals also regulate ?- cell growth. 3. Test the hypothesis that autocrine BMP4 signals regulate adult ?-cell growth. To carry out our studies we will employ techniques that are fully implemented in our laboratory, supported by substantial preliminary data. Thus, we anticipate that our studies could establish BMPs as a major mitogenic signaling pathway in ?-cells. Importantly, an FDA approved BMP2 drug is already in routine clinical use to speed healing of bone fractures. These studies could ultimately lead to novel BMP based therapies for diabetes patients. NARRATIVE: Improved understanding of beta-cell growth is an important diabetes research goal that could benefit diabetes patients, allowing preservation of insulin secretion in patients with type 2 diabetes, or expansion of islets for transplant into patients with type 1 diabetes. Here, we propose studies to genetically interrogate the role of the Bone Morphogenic Protein (BMP) signaling pathway in beta-cell growth, a novel strategy that could lead to the development of new therapies for diabetes.
|Sartori, Daniel J; Wilbur, Christopher J; Long, Simon Y et al. (2014) GATA factors promote ER integrity and *-cell survival and contribute to type 1 diabetes risk. Mol Endocrinol 28:28-39|
|Tuttle, Alex H; Rankin, Matthew M; Teta, Monica et al. (2010) Immunofluorescent detection of two thymidine analogues (CldU and IdU) in primary tissue. J Vis Exp :|
|Rankin, Matthew M; Kushner, Jake A (2009) Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes 58:1365-72|
|He, Lu Mei; Sartori, Daniel J; Teta, Monica et al. (2009) Cyclin D2 protein stability is regulated in pancreatic beta-cells. Mol Endocrinol 23:1865-75|