Development Of Novel Diabetes Therapies Based On Neutralizing FSTL3 Activity

DESCRIPTION provided by applicant Both type and type diabetes involve loss of insulin producing pancreatic cells resulting in inadequate insulin secretion to control blood glucose Eventually daily injections of insulin are required to avoid the constellation of pathologies that arise from hyperglycemia While transplantation of cadaveric pancreatic islets that contain cells has been successful for treating a small number of type diabetic patients the supply is far too limited Production of functional cells from embryonic stem cells remains an exciting possibility for future treatments but will still involve transplantation with immune protection unless patient specific cells can be produced Induction of proliferation in remainin cells has progressed in rodent studies but has not yet been successfully adapted for human cells Recently both human and mouse islet cells have been demonstrated to undergo transdifferentiation to different cell types demonstrating a previously unappreciated flexibility i cell fate Therefore expansion of endogenous cell mass through enhancing transdifferentiation of cells into functional cells represents an appealing potential therapetic solution to restoring glucose control Our prior research has identified the activin signaling pathway and its regulation by a natural antagonist FSTL as having influence on islet cell fate such that loss inhibition of FSTL FSTL KO mouse results in expansion of cell mass and islet size resulting in improved glucose regulation Preliminary results suggests that this cel expansion is due at least in part to increased to cell transdifferentiation Therefore th long term goal of Fairbanks Pharmaceuticals is to identify antagonists of FSTL that will replicate the phenotype of the FSTL KO mouse and thus have therapeutic potential The research proposed here will address the clinical need for new diabetes therapies by developing a series of candidate FSTL antagonists that will be screened for antagonist activity specificity binding sites and other characteristics required for a patent application Specific Aim The net effect of FSTL neutralization will be increased activin bioactivity which will be detected using an in vitro bioassay in which luciferase expression is enhanced in the presence of activin signaling This assay will be used to screen panels of inhibitors to identify the most active candidates The top ranking antagonists will then be tested for biological function in vitro using human and mouse islets Specific Aim Together the two Specific Aims will identify the top to candidate FSTL neutralizing compounds that will be tested in vivo in Phase using animal models of diabetes as well as transplanted human islets Successful FSTL antagonists can then be tested in clinical trials for effectiveness in treating diabetes in humans during Phase activities The ultimate goal is to produce a transformative diabetes therapy that can increase the number of a patientandapos s own cells to restore glucose control and thus reduce or eliminate diabetes PUBLIC HEALTH RELEVANCE The proposed research is relevant to public health because it addresses the critical issue of developing new treatments for diabetes a major national health care concern These patients cannot synthesize sufficient insulin to control blood glucose leading to life long health complications The research proposed here will capitalize on our prior research through development of a new therapy that will stimulate replacement of lost insulin producing cells with potential to reduce or eliminate diabetes