Gene Circuits that Control Morphology in Histoplasma

控制组织胞浆菌形态的基因电路

• 批准号: 7060778
• 负责人: Anita Sil
• 金额: $ 29.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7060778
• 关键词: Histoplasma; environmental adaptation; functional /structural genomics; fungal genetics; gene expression profiling; genetic screening; high throughput technology; microorganism growth; morphology; temperature; virulence

DESCRIPTION (provided by the applicant): Fungal infections are a growing medical threat, particularly for immunocompromised individuals. A molecular understanding of how fungal pathogens sense and respond to their environment will strengthen our ability to identify the Achilles' heel of these organisms for therapeutic purposes. The long-term goal of this research project is to determine how environmental signals regulate morphology and virulence in the fungal pathogen Histoplasma capsulatum. H. capsulatum grows in a filamentous mold (mycelial) form in the soil and a budding yeast form in the host. The transition from the mycelial form to the yeast form is thought to be essential for virulence. Although temperature is known to be a key signal that triggers the conversion between the two forms of H. capsulatum, little is known about the molecular mechanism of how temperature regulates morphology. We hypothesize that H. capsulatum uses conserved signal transduction pathways converging on master transcription factors to regulate morphology in response to temperature. The objective of this proposal is to use genetics and functional genomics to identify key molecules that are required for this process. Our specific aims are (1) to perform a genetic screen using a high throughput colony morphology assay to identify genes required for normal morphology in response to temperature; (2) to use gene expression profiling as a sensitive assay to characterize the function of regulators of morphology; and (3) to further characterize the function of putative regulators of morphology using molecular genetic experiments such as gene inactivation, ectopic expression, and subcellular localization. These studies will generate an understanding of the regulatory circuits used by H. capsulatum to shift its growth program in response to environmental signals. Moreover, the proposed research will elucidate the mechanism of how H. capsulatum regulates virulence properties in response to temperature.

描述（由申请人提供）：真菌感染是日益增长的医疗威胁，特别是对于免疫功能低下的人。对真菌病原体的感知和对环境的反应的分子理解将增强我们出于治疗目的鉴定这些生物的跟腱的能力。该研究项目的长期目标是确定环境信号如何调节真菌病原体组织囊肿的形态和毒力。 H. capsulatum在土壤中以丝状霉菌（菌丝体）形式生长，并在宿主中生长出萌芽的酵母菌形式。从菌丝形式到酵母形式的过渡被认为对毒力至关重要。尽管已知温度是触发两种形式的H. capsulatum之间转换的关键信号，但对于温度如何调节形态的分子机制知之甚少。 我们假设H. capsulatum使用保守的信号转导途径在主转录因子上融合以调节对温度的形态。该提案的目的是使用遗传学和功能基因组学来识别此过程所需的关键分子。我们的具体目的是（1）使用高吞吐量菌落形态测定法进行遗传筛选，以鉴定正常形态对温度的响应所需的基因； （2）使用基因表达分析作为一种敏感测定，以表征形态调节剂的功能； （3）使用分子基因实验（例如基因失活，异位表达和亚细胞定位）进一步表征了形态学调节剂的功能。这些研究将产生对囊膜链球菌使用的调节回路的理解，以响应环境信号，以转移其增长计划。此外，拟议的研究将阐明H. capsulatum如何根据温度调节毒力性能的机制。