Cellular Mechanisms Governing an Invasive Aspergillosis Virulence Factor

控制侵袭性曲霉病毒力因子的细胞机制

• 批准号: 7803335
• 负责人: Graeme S Garvey
• 金额: $ 2.17万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803335
• 关键词: Anabolism; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Binding; Biological; Biological Models; Chemicals; Complex; Development; Disease; Future; Gene Cluster; Gene Deletion; Gene Expression; Genes; Genetic Screening; Goals; Histones; Human; Immunocompromised Host; Impairment; Investigation; Knowledge; Length; Light; Link; Metabolism; Methionine; Methylation; Methyltransferase; Modeling; Molds; Mus; Mycoses; N-terminal; Nuclear; Organism; Orthologous Gene; Pathogenesis; Phagocytosis; Predisposition; Production; Proteins; Proteome; Proteomics; Regulation; Regulator Genes; Regulatory Element; Reproduction spores; Research; Role; Sequence Homology; Sterigmatocystin; Toxic effect; Toxin; Transcriptional Regulation; Virulence; Virulence Factors; Work; base; chromatin protein; chromatin remodeling; effective therapy; fungus; genetic regulatory protein; in vivo; interest; member; mortality; mutant; neutrophil; pathogen; reconstitution; remediation

DESCRIPTION (provided by applicant): Secondary metabolites produced by filamentous fungi represent an enormous reservoir of natural chemical diversity. These non-essential compounds are often employed by the producing fungi in defense and pathogenesis. Impairment of secondary metabolite production in the opportunistic human pathogen Aspergillus fumigatus by deletion of a global regulatory gene, laeA, reduces this organism's virulence. The gene product of laeA is part of a large nuclear regulator complex that links light responsive development and secondary metabolism in Aspergilli and other pathogenic genera. The silencing of secondary metabolite production, decrease of spore production, and reduced virulence In AlaeA strains makes LaeA an excellent target for reducing the mortality rates of IA and other fungal diseases. The mechanism of LaeA regulation of secondary metabolism has remained elusive. The overall goal of this proposal is to elucidate the mechanism of LaeA function. Specific aims to achieve this goal include 1) to further biochemically characterize the methyltransferase activity of this gene product. 2) to identify the chromatin protein interactors involved with LaeA regulation of gene clusters 3) to develop and implement a forward genetics screen to identify potential LaeA targets required for secondary metabolite cluster expression. Relevance: Aspergillus fumigatus, a ubiquitous environmental fungus, is the primary causal agent of invasive aspergillosis. Current treatments with antifungal agents is often ineffective with invasive aspergillosis mortality rates still unacceptably high, it is therefore necessary to continue targeting other virulence attributes of A. fumigatus, such as LaeA governing of secondary metabolite production. Knowledge gained from this study could benefit future efforts in developing effective treatments of fungal infections.

描述（由申请人提供）：丝状真菌生产的二级代谢产物代表了自然化学多样性的巨大储层。这些非必需的化合物通常由生产真菌在防御和发病机理中使用。通过删除全球监管基因LAEA的降低了机会性人类病原体曲霉曲霉中的继发代谢产物的损害，LAEA降低了这种生物体的毒力。 LAEA的基因产物是大型核调节剂复合物的一部分，该复合物将曲曲霉和其他致病属的光反应性发育和继发代谢联系起来。二次代谢产物产生的沉默，孢子产生的减少以及降低ALAEA菌株的毒力使LAEA成为降低IA和其他真菌疾病死亡率的绝佳目标。继发代谢的LAEA调节机制仍然难以捉摸。该提案的总体目标是阐明LAEA功能的机制。实现此目标的具体目的包括1）进一步的生化表征该基因产物的甲基转移酶活性。 2）确定与基因簇的LAEA调节有关的染色质蛋白相互作用3）开发和实施正向遗传筛选，以识别次级代谢物簇表达所需的潜在的LAEA靶标。 相关性：无处不在的环境真菌曲霉曲霉是侵袭性曲霉菌病的主要原因。当前用抗真菌剂的治疗通常无效，侵入性的曲霉病死亡率仍然无法接受，因此有必要继续靶向烟曲霉的其他毒力属性，例如继发代谢物产生的宣布。从这项研究中获得的知识可以使未来在开发真菌感染有效治疗的努力中受益。