Gene Circuits that Control Morphology in Histoplasma

描述（由申请人提供）：真菌感染是一种日益增长的医学威胁，特别是对免疫功能低下的个体。对真菌病原体如何感知和响应其环境的分子理解将加强我们识别这些生物体的阿喀琉斯之踵的能力，以用于治疗目的。本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荚膜组织浆体的形态和毒力。荚膜菌在土壤中以丝状霉菌（菌丝）的形式生长，在寄主体内以芽殖酵母的形式生长。从菌丝形态到酵母形态的转变被认为是毒力的必要条件。虽然已知温度是触发两种荚膜荚膜菌之间转化的关键信号，但对温度如何调节形态的分子机制知之甚少。

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.