Coordinated Regulation of Virulence Genes in C. neoformans

新型隐球菌毒力基因的协调调控

• 批准号: 8668884
• 负责人: ANDREW ALSPAUGH
• 金额: $ 38.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668884
• 关键词: Acquired Immunodeficiency Syndrome; Adenylate Cyclase; Bioinformatics; Biological Models; Biological Process; Carbon; Cell physiology; Cellular Stress; Cellular Stress Response; Communicable Diseases; Consensus Sequence; Cryptococcus neoformans; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Elements; Environment; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Gene Expression; Genes; Genetic Transcription; Human; Infection; Infectious Agent; Iron; Melanins; Modeling; NRG1 gene; Organism; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Polysaccharides; Process; Production; Promoter Regions; Proteins; Regulation; Regulatory Element; Research Personnel; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Source; Stimulus; Stress; Surface; System; Testing; Transcription factor genes; Virulence; Yeasts; capsule; comparative; design; environmental change; gene function; insight; man; microbial; microorganism; novel; pathogen; research study; response; transcription factor

DESCRIPTION (provided by applicant): To survive within the hostile environment of the infected host, pathogenic microorganisms must be able to sense and adapt to changing environmental conditions. This adaptation requires the coordinated regulation of multiple cellular factors. Like many infectious agents, the human fungal pathogen Cryptococcus neoformans uses the conserved signaling molecule cyclic AMP (cAMP) to regulate its response to external stresses. The central components of cAMP signal transduction pathways are highly conserved among microorganisms. However, the main hypothesis of this proposal is that the upstream activating signals and the downstream effectors of cAMP are functionally specialized in microbial pathogens. This specialization allows pathogenic organisms to use cAMP signaling to specifically control their virulence potential. Over the past several years, we have demonstrated that the C. neoformans cAMP pathway is required for adaptation to the host environment. This pathway regulates the induction of capsule and melanin, two cellular factors required for pathogenesis. This regulation occurs primarily at the level of transcription. Therefore, we designed the experiments of this proposal to identify trans- and cis-acting regulatory elements that control the transcription of capsule-associated genes. Specific Aim 1 proposes bioinformatic and transcriptional profiling approaches to identify transcription factors that control C. neoformans capsule gene expression. Specific Aim 2 outlines detailed testing of selected transcriptional regulators to define their role in capsule induction. Experiments in Specific Aim 3 will define the direct and indirect target genes of the transcription factors identified in the first two Aims. Upon completion, these experiments will offer new insight into the ways in which this specific pathogen senses and responds to its host. By defining new functions for conserved signaling pathways, these experiments will also explore broader issues in environmental sensing, cellular stress, and microbial virulence.

描述（由申请人提供）：为了在感染宿主的敌对环境中生存，致病性微生物必须能够感知并适应不断变化的环境条件。这种适应需要对多种细胞因子进行协调的调节。像许多传染性药物一样，人类真菌病原体Neoformans使用保守的信号传导分子环状AMP（CAMP）来调节其对外部应力的反应。在微生物中，cAMP信号转导途径的中心成分是高度保守的。但是，该提案的主要假设是上游激活信号和CAMP的下游效应子在功能上专门用于微生物病原体。这种专业允许致病生物使用cAMP信号传导专门控制其毒力潜力。在过去的几年中，我们已经证明，适应宿主环境所需的C. Neoformans Camp Pathway是必需的。该途径调节胶囊和黑色素的诱导，这是发病机理所需的两个细胞因子。该调节主要发生在转录水平。因此，我们设计了该提案的实验，以识别控制胶囊相关基因转录的反式和顺式调节元件。特定目标1提出了生物信息学和转录分析方法，以鉴定控制新生虫囊囊基因表达的转录因子。特定目标2概述了选定的转录调节器的详细测试，以定义其在胶囊诱导中的作用。特定目标3中的实验将定义前两个目标中确定的转录因子的直接和间接目标基因。完成后，这些实验将对这种特定病原体感知并对其宿主做出反应的方式提供新的见解。通过定义保守信号通路的新功能，这些实验还将探索环境传感，细胞应激和微生物毒力方面的更广泛问题。