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Endocrinology, Diabetes Mellitus.

Insulin-like growth factor (IGF)-I is a peptide hormone mainly produced from the liver and other tissues at lower and variable levels. Research of last two decades 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 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 a recent study 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 CCN5 overexpression accelerates the proliferation of insulinoma cells, activate signaling molecules Akt and/or Erk1/2 kinases, and CCN5 overexpression prevent 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. We propose to establish a direct stimulation of CCN5 gene expression by IGF-I, the effects of in vitro administration of recombinant CCN5 on pancreatic islet cell proliferation and survival against harsh conditions, in vivo stimulation on pancreatic islet regeneration after removing part of the pancreas, and in vivo protection of CCN5 protein against experimental diabetes in mice. These studies will aid in the design of novel and potentially more effective therapeutic approaches exploiting CCN5 and its molecular targets, in improving the survival and function of the pancreatic islet cells.

On the other hand, we have (re)discovered the role of Reg proteins in diabetes, pancreatitis and pancreatic cancer. We study the role of Reg family proteins in pancreatic ductal adenocarcinoma (PDAC). Reg family proteins are normally expressed in the pancreas, some of which are known to promote cell proliferation and survival, are secreted and can be detected in serum. We discovered isoform- and cell-specific overexpression in ductal cancer cells, which might serve as specific markers for disease in diagnosis and treatment. The overexpression is also associated with acinar to ductal metaplasia (ADM), a possible cause of cancer origin. We hypothesize that increased expression of Reg proteins promote the development of ADM, PDAC or metastasis into extra pancreatic sites, thus can be targeted for cancer intervention, diagnosis or therapeutic monitoring. We propose (1) to screen for isoform-specific expression of Reg proteins in pancreatic cancer, (2) to correlate Reg protein expression with disease stage and other known markers, and (3) to study possible effect of Reg proteins in promoting ADM and cancer growth in cultured pancreatic cancer cells or in mutant laboratory mice.