Nonalcoholic Steatohepatitis Therapies from the Ubiquitin Pathway

Nonalcoholic steatohepatitisNASHis a serious health condition associated with the accumulation of lipids in the liver which leads to chronic inflammationThis inflammation can predispose affected individuals to serious downstream health problems including cirrhosis and hepatocellular carcinomaNASH occurs in a wide variety of patients but has a number of known risk factorsincludingobesityglucose intoleranceand metabolic syndromeWhile the majority of patients are betweenandyears oldthe increasing prevalence of obesity has made NASH a concern for all age groupsDespite these known risk factorsno pharmacologic interventions existand current therapies focus primarily on changes to lifestyle to try and mitigate steatosis in the liver and the development of fibrosis and inflammation that stems from itThis fibrotic phenotype is of particular concern as it appears to activate potent immune responses that underlie the inflammatory phenotype which portends eventual cirrhosisThe fibrotic and inflammatory responses are complex in NASH but are at least partially reflective of NFB mediated signaling events which regulate a number of pro inflammatory cytokines secreted by steatotic hepatocytesThe ubiquitin proteasome system plays an important role in regulating NFB signalingin particular through the deubiquitnase CYLDAs a down regulator of both canonical and non canonicals NFB signalingCYLD has been shown to be an important protective factor against NASHCYLD is regulated by the ELigase TRIMwhich mediates its degradationAs suchinhibition of TRIMwould stabilize CYLD and likely mitigate the detrimental effects of NFB signaling in NASHPhase I of this grant would focus on the development of HTS assays to identify TRIMinhibitors which can stabilize CYLD and mitigate the development of steatosis in response to lipotoxicityPhase II will focus on hit to lead development and the evaluation of lead compounds in animal models of NASHThe ultimate commercial goal of this project is the identification of small molecule TRIMinhibitors In non alcoholic steatohepatitisNASHlipids accumulate in the liver and produce chronic inflammationwhich can result in serious and life threatening liver disordersthere is currently no cureRecentlya ubiquitin protease called CYLD has been shown to protect against development of NASHit can be removed from cellshoweverby a ubiquitin ligase called TRIMwhich causes its degradationThis application proposes to develop selective inhibitors of TRIMthat will protect CYLD in cells and thereby provide benefit for patients with NASH