SET DOMAIN EPIGENETIC FACTORS GOVERN ANTIFUNGAL DRUG EFFICACY AND FUNGAL PATHOGENESIS

Project Summary/Abstract:In recent years, a significant increase in mortality of patients with microbial fungal infections has beenobserved. This is primarily due to a higher incidence of individuals who are immunocompromisedincluding HIV-infected patients, patients undergoing cancer therapy, organ transplant recipients, andpatients with advanced stages of diabetes. A complication in treating patients with fungal infections isthe development of multidrug-resistant fungi. With the limited number of effective antifungal drugs, theincrease of drug resistant fungi, and development of new pathogenic fungi, fungal infections are amajor threat to human health. The proposed studies help to solve this issue by identifying underlyingcauses for drug resistance and to identify additional molecular targets for development of newantifungal drugs that will effectively treat fungal infections or work in combination with currenttreatments. Our central hypothesis is that SET domain epigenetic factors regulate genes or pathwaysthat alter antifungal drug resistance. This hypothesis was established based on our preliminaryobservations showing that loss of SET domain coding genes such as SET1, SET3, and SET4 canalter the efficacy of antifungal drugs. This proposal will use S. cerevisiae, the opportunistic pathogen,C. glabrata, and G. mellonella larvae as model systems to identify key epigenetic regulators and tostudy the impact of epigenetics and epigenetic factors on antifungal drug resistance and pathogenicity.The epigenetic mechanisms that regulate the expression of genes and pathways important forantifungal drug resistance will be identified, a new precursor sterol pathway will be characterized, andthe biological and biochemical function of the newly defined epigenetic factor, Set4 will be determined.Overall, studying SET domain proteins and other epigenetic factors will have a positive impact onpublic health by providing fundamental new insights in the areas of fungal infections and antifungaldrug resistance.