Mitochondrial TAT-DNA repair proteins for treatment of insulin resistance

DESCRIPTION provided by applicant Insulin resistance IR also known as metabolic syndrome is tied to obesity and is associated with numerous modern health problems including the growing problems of type diabetes and cardiovascular disease The growing health economic and social burdens of these conditions calls for the need to develop drug treatments for IR We know from multiple lines of evidence that mtDNA serves as a molecular sentinel controlling cell fate in response to oxidant stress There is a conspicuous association between mtDNA damage and oxidant induced cell death the propensity for cytotoxicity is inversely related to the efficiency of mtDNA repair Also a growing body of evidence suggests that integrity of mitochondrial DNA mtDNA is crucial in the IR progression The mtDNA is highly specialized and encodes for proteins essential for energy metabolism and free radical production very critical for insulin signaling With respect to IR we have found that the extent f mtDNA damage directly correlates to obesity induced IR Using a genetic approach the targeting of Exscienandapos s fusion protein construct Exscien I to mitochondria containing the DNA repair enzyme human oxoguanine DNA glycosylase hOGG has shown to significantly improve insulin sensitivity in transgenic MTS hOGG mice Essentially by overexpressing the repair enzyme at the point of oxidative stress we have attenuated the level of mtDNA damage and the IR side effects We now propose to fully verify the level of efficacy of mitochondria targeted DNA repair andquot drugsandquot in the obesity induced mouse model of IR The intent of this Phase I proposal is to establish proof of concept that pharmacologic enhancement of mtDNA repair attenuates the degree of IR This proposed application is innovative because it will herald first in class molecules directed against a novel target in metabolic syndrome mtDNA

PUBLIC HEALTH RELEVANCE There are currently limited pharmacologic interventions to treat insulin resistance In a related context while reactive oxygen species play a known role in insulin resistance non selective anti oxidants have proven ineffective Herein we will validate a
new concept that the repair of oxidative mtDNA damage directs cell fate decisions in insulin resistance which if holds will point to an entirely new pharmacologic strategy for treating insuln resistance and associated cardiovascular disorders