SET Domain Epigenetic Factors Govern Antifungal Drug Efficacy and Fungal Pathogenesis

项目摘要/摘要： 近年来，微生物真菌感染患者的死亡率显著增加。 观察到的。这主要是由于免疫功能受损的个体发病率较高。 包括艾滋病毒感染者，接受癌症治疗的患者，器官移植接受者，以及 糖尿病晚期患者。治疗真菌感染患者的一个并发症是 多重耐药真菌的发展。由于有效的抗真菌药物数量有限， 耐药真菌的增加，以及新致病真菌的发展，真菌感染是一种 对人类健康的重大威胁。拟议的研究有助于解决这一问题，因为它确定了 耐药的原因和寻找新的开发新的分子靶点 可有效治疗真菌感染的抗真菌药物或与当前 治疗。我们的中心假设是，设定的表观遗传因子调控基因或途径 改变了抗真菌药物的耐药性。这一假设是基于我们初步的 观察表明，SET1、SET3和SET4等SET结构域编码基因的丢失可以 改变抗真菌药物的疗效。这项提案将使用酿酒酵母，这是一种条件致病菌， 和梅氏微囊藻幼虫作为模式系统，以识别关键的表观遗传调控因子，并 研究表观遗传学和表观遗传学因素对抗真菌耐药性和致病性的影响。 调控基因和通路表达的表观遗传机制 将确定抗真菌耐药性，将表征一种新的前体类固醇途径，以及 新定义的表观遗传因子Set4的生物学和生化功能将被确定。 总体而言，研究SET结构域蛋白和其他表观遗传因素将对 通过在真菌感染和抗真菌领域提供基本的新见解来促进公共卫生 抗药性。

Project Summary/Abstract: In recent years, a significant increase in mortality of patients with microbial fungal infections has been observed. This is primarily due to a higher incidence of individuals who are immunocompromised including HIV-infected patients, patients undergoing cancer therapy, organ transplant recipients, and patients with advanced stages of diabetes. A complication in treating patients with fungal infections is the development of multidrug-resistant fungi. With the limited number of effective antifungal drugs, the increase of drug resistant fungi, and development of new pathogenic fungi, fungal infections are a major threat to human health. The proposed studies help to solve this issue by identifying underlying causes for drug resistance and to identify additional molecular targets for development of new antifungal drugs that will effectively treat fungal infections or work in combination with current treatments. Our central hypothesis is that SET domain epigenetic factors regulate genes or pathways that alter antifungal drug resistance. This hypothesis was established based on our preliminary observations showing that loss of SET domain coding genes such as SET1, SET3, and SET4 can alter 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 to study 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 for antifungal drug resistance will be identified, a new precursor sterol pathway will be characterized, and the 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 on public health by providing fundamental new insights in the areas of fungal infections and antifungal drug resistance.