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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要：近年来，微生物真菌感染患者的死亡率显着增加观察到。这主要是由于免疫受损的个体的发病率更高包括感染HIV的患者，接受癌症治疗的患者，器官移植受者和患有晚期糖尿病的患者。治疗真菌感染患者的并发症是多药耐药真菌的发展。由于有效抗真菌药物的数量有限，耐药菌的增加以及新的致病真菌的发展，真菌感染是一种对人类健康的主要威胁。拟议的研究通过识别潜在的研究有助于解决此问题耐药性的原因，并确定开发新的分子靶标抗真菌药物将有效治疗真菌感染或结合当前治疗。我们的中心假设是固定域表观遗传因子调节基因或途径这改变了抗真菌耐药性。该假设是根据我们的初步建立的观察结果表明，set1，set3和set4等集合域编码基因的丢失可以改变抗真菌药物的功效。该建议将使用酿酒酵母，机会性病原体， C. glabrata和G. mellonella幼虫作为模型系统，以识别关键的表观遗传调节剂并进行研究表观遗传学和表观遗传因素对抗真菌耐药性和致病性的影响。调节基因和途径表达的表观遗传机制对于将确定抗真菌耐药性，将表征新的前体固醇途径，并将确定新定义的表观遗传因子的生物学和生化功能SET4。总体而言，研究固定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，通过提供新的新见解耐药性。