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: 10229440
• 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/10229440
• 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; 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; 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; opportunistic pathogen; overexpression; paralogous gene; 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.

项目总结/文摘: