Sexual development in Cryptococcus neoformans

描述（由申请方提供）：本提案的目的是确定人类机会性真菌病原体新型隐球菌中控制性发育的分子机制。有性发育导致孢子的产生，这些孢子可以散布到环境中。C.据认为，新形菌通过呼吸道从环境来源感染人类，其中真菌孢子被吸入肺的肺泡。一旦吸入，C.新型脑膜炎病毒可扩散至中枢神经系统，引致致命的脑膜炎。了解C. neoformans有望为隐球菌病的预防和/或治疗提供有用的信息。这项研究也是普遍感兴趣的，因为机会性真菌是新兴的病原体：了解基本的真菌生物学为开发更有效的预防和治疗真菌疾病的方法奠定了基础。In C.性诱导基因SXI 1a和SXI 2a控制新生儿的性发育，但它们的作用机制尚不清楚。本提案中概述的实验旨在阐明SXI 1a和SXI 2a调节基因表达以驱动性分化的机制。利用遗传学、生物化学、生物信息学和细胞生物学方法，我们将1）通过识别和表征Sxi 1a和Sxi 2a的下游靶点来绘制由它们控制的调控回路，2）通过评估它们的结构和功能之间的关系来建立控制性发育所需的Sxi 1a和Sxi 2a蛋白的特性，和3）研究性发育所需的细胞过程，特别关注发育。这里提出的不同方法将阐明性发育的早期阶段，并提供新的见解如何感染性颗粒的生产发生在C。新人类

DESCRIPTION (provided by the applicant): The goal of this proposal is to determine the molecular mechanisms by which sexual development is controlled in the opportunistic human fungal pathogen Cryptococcus neoformans. Sexual development results in the production of spores that can be dispersed into the environment. C. neoformans is thought to infect humans from environmental sources via a respiratory route in which fungal spores are inhaled into the alveoli of the lungs. Once inhaled, C. neoformans can disseminate to the central nervous system and cause a fatal form of meningitis. Understanding the biology of sexual development and spore production in C. neoformans promises to provide information useful in the prevention and/or treatment of cryptococcal disease. This study is also of general interest because opportunistic fungi are emerging pathogens: understanding basic fungal biology sets the stage for the development of more effective methods of preventing and treating fungal disease in general. In C. neoformans sexual development is controlled by the Sex Inducer genes, SXI1a and SXI2a, but the mechanism by which they act is unknown. The experiments outlined in this proposal are designed to elucidate the mechanism by which SXI1a and SXI2a regulate gene expression to drive sexual differentiation. Using genetic, biochemical, bioinformatic, and cell biological approaches we will 1) map the regulatory circuit controlled by Sxi1a and Sxi2a by identifying and characterizing their downstream targets, 2) establish the properties of the Sxi1a and Sxi2a proteins required to control sexual development by evaluating the relationships between their structures and functions, and 3) investigate the cellular processes required for sexual development with a specific focus on dikaryotic filamentation. The diverse approaches presented here will elucidate the early stages of sexual development and lend new insights into how infectious particle production occurs in C. neoformans.