Regulation of Autoimmune Type 1 Diabetes by Serpins B1 and A1 (Alpha 1-Antitrypsin)

The number of people with diabetes worldwide is predicted to increase frommillion intomillion inThe health care costs of treating the disease account forof the global health expenditure and continue to be a huge economic burdenIDF World AtlasTypediabetes mellitusT DMconstitutesof the disease burdenIt is an autoimmune diseasethought to be triggered by genetic or environmental factors in early childhoodwhich results in antibodymediated destruction of insulin producing pancreaticcells causing life threatening hyperglycemiaIn contrasttypediabetes mellitusT DMdevelops later in life and results from insulin resistance in target tissues and inflammation coupled with an inadequate compensation by thecellsA major limitation in effectively treating both forms of the disease is preventing a decline incell function and or massRecentlythe Kulkarni lab identified Serpin Ban intracellular SERine Proteinase Inhibitoras a liver derived protein factor that promotes a compensatorycell response by inhibiting elastase and inducingcell proliferation in multiple species by activating growth survival factor signaling pathwaysThe structurally and functionally related human plasma protein alphaantitrypsinAATserpin Ais in late stage clinical trials to delay the onset of T DM after a majority of independent studies showed it could restore euglycemia in animal models of T DM by preserving functionalcellsenhancing islet allograft survival and modulating cellular immunityEarly stage clinical study results indicate that AAT reduces HbA c levels and anti islet cell antibody titersSerpin BsBlike AATis an effective anti inflammatory elastase inhibitor but unlike AATalso inducescell proliferationpromotes insulincells in pancreatic ductal lining epitheliainhibits NETosisanother pro inflammatory process involved in diabetesand regulates the expansion of Thcytokine producing cells in vitroWe therefore propose that sBmay also work in vivoeither alone or in combination with AATto provide superior therapeutic effects in animal models of T DMWe will test if sBAAT can more effectively prevent the onset ofor treat establishedT DM in the NOD mouse model by inducing proliferation of functionalcellsenhancing production of insulin by ductal lining cells and protectingcells from the immune responseIf successfulwe will further develop this technology through preclinical and clinical testing with the intent to improve long term outcome for patients with T DMThe proposed research in phase I will focus onAimproducing highly purified active recombinant proteins andAimproviding proof of principle in animal models of T DMThe outcome of these studies will guide the design of future efficacy studies in animals and humans A major focus in preventing or reversing the onset of typediabetes mellitusT DMis the preservation of functional insulin producing pancreatic isletcells through approaches designed to either enhance proliferation ofcells or dampen the immune response targetingcellsWe and others have demonstrated that the human protein serpin Bpromotescell proliferationinduces insulin production in pancreatic ductal cells and regulates the Thmediated cytokine response in vitroWe seek to confirm these findings in vivo in the commonly used and well accepted NOD mouse model of T DM to determine if use of serpin Bas a biological agent aloneor in combination with another promising late stage anti inflammatory and immuno regulatory clinical candidatealphaantitrypsinAATcan more effectively prevent the onset ofor treat established T DM thus restoring euglycemiaand dramatically enhancing patient healthquality of lifeand long term survival