Grant: Project Grant

Pancreatic beta cells secrete insulin which controls energy metabolism; lack of beta cells and/or insulin secretion causes diabetes mellitus. Studies on the regeneration of pancreatic islets, using animal models, represent a major effort leading to a cure of this deadly disease. Insulin-like growth factor (IGF)-I is a peptide hormone mainly produced from the liver. Research of last decade by us and others has established that IGF-I is a potent growth factor for pancreatic islet cells, promotes cell survival and prevents onset of experimental diabetes. In order to explore where and how IGF-I acts on the islet cells, we have screened and identified the molecular targets using the technique of whole genome cDNA microarray. Prominently among the 82 preliminary targets we have discovered, CCN5/WISP2 has never been known to be expressed by the islet cells nor regulated by IGF-I. In 2 recent studies we have shown that CCN5 is normally expressed in islet beta cells, IGF-I directly stimulates its gene expression, and IGF-I overexpression caused increased level in the islets. We further demonstrate that CCN5 overexpression accelerates the proliferation of insulin-producing tumor cells, activates signaling molecules FAK, Akt and Erk1/2 kinases, and CCN5 overexpression prevents cell death. We thus hypothesize that CCN5 is normally expressed by islet beta cells and activated by IGF-I, its increased production promotes islet cell proliferation and regeneration, and survival, in concert to the action of IGF-I itself. Here, we propose to characterize the change in pancreatic beta cells after knocking out the production of CCN5; to establish that CCN5 treatment promotes beta cell growth or expansion in culture; to characterize a cell surface receptor which interacts with CCN5 and mediates its actions; and to test the therapeutic potential of CCN5 in preclinical, rodent diabetes. The findings will provide a fundamental insight into islet cell biology and lead for designing therapies.