Regulatory circuits that link cell fate and virulence in Histoplasma capsulatum

荚膜组织胞浆菌中连接细胞命运和毒力的调节回路

基本信息

批准号：
8751163
负责人：
Sinem Beyhan
金额：
$ 12.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8751163
关键词：
Advisory Committees Affect Award Binding Bioinformatics Biological Process Body Temperature Body Temperature Changes Breathing Candidate Disease Gene Cell Shape Cells Cellular Morphology Collaborations Committee Members Complement Complement Factor H Complex Cues DNA DNA Binding Data Disease Fibrinogen Filament Funding Gene Expression Genes Genome Goals Growth Health Histoplasma capsulatum Human Human body Immunocompetent Immunocompromised Host Immunoprecipitation Individual Infection Infectious Agent Laboratories Learning Light Link Lung Maintenance Mass Spectrum Analysis Mentors Microbial Biofilms Mining Modeling Molds Molecular Morbidity - disease rate Morphogenesis Mus Mycoses Occupations Organism Orthologous Gene Pathogenesis Pathway interactions Phase Phosphotransferases Physiology Play Positioning Attribute Postdoctoral Fellow Preparation Proteins Publications RNA Interference Regulation Reproduction spores Research Research Personnel Respiratory Tract Infections Role Saccharomycetales Secure Soil Source Stimulus Stress System Systemic infection Techniques Temperature Temperature Sense Testing Therapeutic Training Transcript Universities Virulence Virulence Factors Work Yeasts base cell motility chromatin immunoprecipitation fascinate functional genomics fungus genetic regulatory protein interest macrophage microorganism mortality mutant novel particle pathogen prevent professor programs protein-histidine kinase public health relevance research study response transcriptome sequencing yeast protein yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Histoplasma capsulatum is one of several systemic dimorphic fungal pathogens that switch their growth program from an infectious mold form in the soil to a pathogenic yeast form in mammalian hosts. H. capsulatum causes up to 500,000 infections per year in the U.S. alone, making it the most common cause of fungal respiratory infections in healthy hosts. Infection occurs when the soil is disrupted, facilitating dispersion o hyphal fragments or spores that are inhaled by humans. The morphologic switch between the hyphal and yeast forms is critical to the establishment and maintenance of disease. Spores and hyphal fragments are the primary infectious agents; however, once introduced into the host, the pathogen converts to a budding-yeast form, which survives and replicates within host macrophages. In the laboratory, the switch between the infectious and parasitic states is modeled by changing the temperature: cells grow in the filamentous form at room temperature, whereas growth at 37¿C is sufficient to trigger growth in the yeast form and expression of virulence factors. The long-term research goal of Dr. Beyhan-Pelvan is to understand how H. capsulatum cells sense host temperature and activate the expression of genes required for cell morphology and virulence. Despite its importance to human health, very little is known about how H. capsulatum senses and responds to human body temperature. Dr. Beyhan-Pelvan's prior research findings significantly contributed to the understanding of the molecular mechanism used by H. capsulatum to regulate cell morphology and virulence gene expression: she found that four transcriptional regulators, Ryp1,2,3,4, are the core components of a temperature-responsive intersecting regulatory network. In the mentored phase of this project, Dr. Beyhan-Pelvan aims to use findings from her previous work to identify and characterize novel virulence factors of H. capsulatum. Specifically, downstream targets of the Ryp proteins will be tested for their role in pathogenesis. These studies will also serve as a training opportunity for Dr. Beyhan-Pelvan to learn macrophage and mouse infection techniques. During the independent phase of this award, Dr. Beyhan-Pelvan aims to investigate factors that regulate Ryp proteins in response to host temperature. These studies will provide fundamental information on how cells sense temperature and turn on the appropriate virulence pathways in the host. Findings from this work can be used to investigate how other thermally dimorphic fungi can transition into a pathogenic form in response to host temperature. Ultimately, the information obtained from this project can be used to develop therapeutics for H. capsulatum infections and help prevent other dimorphic fungal infections. Dr. Beyhan-Pelvan has a longstanding interest in studying the molecular mechanisms used by microorganisms to sense and respond to environmental cues to regulate important biological processes (i.e. regulation of cell morphology, biofilm formation, motility or virulence). This project is proposed to complement her research interests and provide her with the required training in virulence studies. Dr. Sil's laboratory provides a unique opportunity to learn experimental techniques required to study both H. capsulatum's pathogenesis and physiology. Dr. Sil offers both funds and support staff to train Dr. Beyhan-Pelvan in macrophage and mouse infections with H. capsulatum. Additionally, as a mentor, Dr. Sil will work closely with Dr. Beyhan-Pelvan to prepare her for academic job searches. Furthermore, co-mentor Dr. Johnson and advisory committee members Drs. Engel, Madhani and Cox, who have facilitated transition of numerous post-doctoral trainees into independent investigators, will provide additional mentoring with emphasis on preparation for job searches and securing a tenure-track assistant professor position in a top-tier research university.

描述（由申请人提供）：荚膜组织胞浆菌是几种系统性二态性真菌病原体之一，其生长程序从土壤中的感染性霉菌形式转变为哺乳动物宿主中的致病性酵母形式，每年导致多达 500,000 例感染。仅在美国，它就成为健康宿主中真菌呼吸道感染的最常见原因。当土壤被破坏时，会促进真菌的传播。人类吸入的菌丝片段或孢子菌丝和酵母形式之间的形态转换对于疾病的形成和维持至关重要。然而，一旦引入宿主，病原体就会发生转变。在实验室中，通过改变温度来模拟感染状态和寄生状态之间的转换：细胞在宿主巨噬细胞内生长。室温下呈丝状，37℃下生长C 足以触发酵母形式的生长和毒力因子的表达 Beyhan-Pelvan 博士的长期研究目标是了解荚膜酵母细胞如何感知宿主温度并激活细胞形态和所需基因的表达。尽管荚膜梭菌对人类健康很重要，但人们对荚膜梭菌如何感知和响应人体温度知之甚少。Beyhan-Pelvan 博士之前的研究结果对理解其分子机制做出了重大贡献。荚膜梭菌用来调节细胞形态和毒力基因表达：她发现四个转录调节因子Ryp1、2、3、4是温度响应性交叉调节网络的核心组成部分。 Beyhan-Pelvan 博士旨在利用她之前的工作发现来识别和表征荚膜螺杆菌的新型毒力因子，具体而言，将测试 Ryp 蛋白的下游靶点在其中的作用。这些研究还将为 Beyhan-Pelvan 博士提供学习巨噬细胞和小鼠感染技术的培训机会。在该奖项的独立阶段，Beyhan-Pelvan 博士旨在研究调节 Ryp 蛋白以响应宿主的因素。这些研究将提供有关细胞如何感知温度并开启宿主中适当的毒力途径的基本信息。这项工作的结果可用于研究其他热二态性真菌如何转变为致病形式。最终，从该项目获得的信息可用于开发荚膜梭菌感染的治疗方法，并帮助预防其他二态性真菌感染。Beyhan-Pelvan 博士长期以来对研究微生物感知和控制宿主温度的分子机制有着浓厚的兴趣。响应环境线索来调节重要的生物过程（即细胞形态、生物膜形成、运动性或毒力的调节）。该项目旨在补充她的研究兴趣，并为她提供所需的培训。 Sil 博士的实验室提供了学习研究荚膜螺杆菌发病机制和生理学所需的实验技术的独特机会。Sil 博士提供资金和支持人员来培训 Beyhan-Pelvan 博士进行巨噬细胞和小鼠感染方面的研究。此外，作为导师，Sil 博士将与 Beyhan-Pelvan 博士密切合作，帮助她为学术求职做好准备。此外，共同导师 Johnson 博士和咨询委员会成员恩格尔、马达尼和考克斯博士帮助众多博士后学员转变为独立研究者，他们将提供额外的指导，重点是为求职做好准备，并在顶级研究型大学获得终身教授助理教授职位。