SET Domain Epigenetic Factors Govern Antifungal Drug Efficacy and Fungal Pathogenesis

SET域表观遗传因素控制抗真菌药物疗效和真菌发病机制

• 批准号: 9790911
• 负责人: SCOTT D BRIGGS
• 金额: $ 38.02万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9790911
• 关键词: Aerobic; Antifungal Agents; Area; Azole resistance; Azoles; Biochemical; Biochemistry; Biological; Biological Assay; Biological Models; Candida glabrata; Cells; Chromatin; Clinical; Code; Complication; Data; Development; Diabetes Mellitus; Disease; Drug Targeting; Drug resistance; Drug usage; Enzymes; Epigenetic Process; Ergosterol; Ethyl Methanesulfonate; Evolution; Expression Profiling; Fluconazole resistance; Foundations; Functional disorder; Fungal Drug Resistance; Gene Expression; Genes; Genetic Transcription; Goals; HIV; Health; Histones; Human; Hypersensitivity; Immunocompromised Host; In Vitro; Incidence; Individual; Knowledge; Lanosterol; Larva; Mediating; Medical; Methylation; Microbial Drug Resistance; Mission; Modification; Molecular Biology; Molecular Target; Multi-Drug Resistance; Mutation; Mycoses; Organ Transplantation; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Predisposition; Production; Protein Precursors; Proteins; Public Health; Publishing; Regulation; Regulatory Pathway; Research; Research Support; SET Domain; Saccharomyces cerevisiae; Sterols; Suppressor Mutations; Tertiary Protein Structure; Transcript; Transplant Recipients; United States National Institutes of Health; Work; Yeasts; antimicrobial; base; cancer therapy; clinically relevant; design; drug efficacy; fungus; genome-wide; histone methyltransferase; histone modification; improved; in vivo; insight; microbial; molecular drug target; mortality; mutant; novel; novel therapeutics; overexpression; paralogous gene; pathogen; pathogenic fungus; targeted treatment; transcriptome sequencing; yeast genetics

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.

项目概要/摘要： 近年来，微生物真菌感染患者的死亡率显著增加， 观察这主要是由于免疫功能低下的个体发病率较高 包括HIV感染者、接受癌症治疗的患者、器官移植受者，以及 晚期糖尿病患者。治疗真菌感染患者的并发症是 多药耐药真菌的发展。由于有效的抗真菌药物数量有限， 随着耐药真菌的增加和新病原真菌的产生，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， 耐药性的原因，并确定其他分子靶标，以开发新的 抗真菌药物，将有效地治疗真菌感染或与目前的 治疗。我们的中心假设是SET域表观遗传因子调节基因或途径 从而改变抗真菌药物的耐药性。这一假设是根据我们的初步研究建立的。 观察表明，SET结构域编码基因如SET 1、SET 3和SET 4的缺失可以 改变抗真菌药物的疗效。该方案将使用S。酿酒酵母菌，机会致病菌， C. glabrata和G.作为模型系统的大蜡螟幼虫，以鉴定关键的表观遗传调节因子， 研究表观遗传学和表观遗传因素对抗真菌药物耐药性和致病性的影响。 调节基因表达的表观遗传机制和重要的途径， 将确定抗真菌药物耐药性，将表征新的前体甾醇途径， 将确定新定义的表观遗传因子Set 4的生物学和生物化学功能。 总的来说，研究SET结构域蛋白和其他表观遗传因素将对 通过提供真菌感染和抗真菌药物领域的基本新见解， 耐药性