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Regulation of Filamentous Growth in Yeast

酵母丝状生长的调控

基本信息

批准号：
8523904
负责人：
Haoping Liu
金额：
$ 33.23万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523904
关键词：
Acetylation Affect Animal Model Antifungal Agents Binding Binding Proteins Biochemistry Biology Candida Candida albicans Candidiasis Cell Nucleus Cellular biology Chromatin Cleaved cell Complex Coupled Cues Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA Binding Domain Deacetylation Defect Development Disseminated candidiasis Dissociation Down-Regulation Environment Farnesol Fluconazole Gastrointestinal tract structure Genes Genetic Epistasis Genetic Transcription Growth Growth and Development function Histone Deacetylase Human Hypersensitivity Hyphae Immune system Immunocompromised Host Individual Infection Integration Host Factors Length Literature Maintenance Mediating Membrane Molecular Molecular Genetics Morphogenesis Morphology N-terminal NRG1 gene Nucleosomes Pathogenesis Pathogenicity Pathway interactions Patients Personal Communication Phase Phosphotransferases Physiology Process Proteins Recruitment Activity Regulation Repression Response Elements Saccharomycetales Serum Signal Pathway Signal Transduction Signal Transduction Pathway Sterols Systemic disease Transcriptional Activation Transcriptional Regulation Vaginitis Virulence Virulence Factors Work Yeasts cell type factor C fungus gut microflora mortality mutant next generation oropharyngeal thrush overexpression pathogen prevent programs promoter response screening transcriptome sequencing

项目摘要

Candida albicans is one of the most frequently isolated fungal pathogens of humans. It can undergo reversible morphogenetic transitions between budding yeast, pseudohyphal, and hyphal growth forms. Its unique ability to switch from yeast to hyphal growth in response to various host and environmental signals is essential to its pathogenicity. Many hypha-specific genes encode virulence factors. Hyphal development is regulated by multiple signal transduction pathways. Among them, the cAMP-dependent protein kinase A (PKA) pathway is a major regulator of morphogenesis and virulence. Despite its importance, the molecular mechanism for how the cAMP-PKA pathway activates the hyphal transcriptional program is still not known. We find cAMP- PKA dependent down-regulation of the major repressor of hyphal morphogenesis, Nrg1, correlates with the initiation of the hyphal transcriptional program. Sustained hyphal transcription requires Hda1 being recruited to the promoters of hypha-specific genes, where it leads to changes in promoter chromatin. We propose to determine the mechanisms and regulators for cAMP-PKA dependent Nrg1 down-regulation upon hyphal induction in Aim 1. Aim 2 defines host factor(s) and C. albicans pathways for the promoter recruitment of Hda1 and its importance in invasive candidiasis. Aim 3 studies functions and regulation of Cph2. A combined approach using molecular genetics, cell biology and biochemistry will be taken in our studies. This work will provide us with a better understanding of how C. albicans integrates various signals to control growth and development, and how it survives and grows in various host environments.

白色念珠菌是人类最常分离的真菌病原体之一。它可以在芽殖酵母之间经历可逆的形态发生转变，假菌丝和菌丝生长形式。其从酵母转变为菌丝的独特能力响应各种宿主和环境信号的生长对其至关重要致病性。许多菌丝特异性基因编码毒力因子。菌丝发育受多种信号转导途径调控。其中， cAMP 依赖性蛋白激酶 A (PKA) 途径是形态发生的主要调节因子和毒力。尽管 cAMP-PKA 很重要，但它的分子机制激活菌丝转录程序的途径仍然未知。我们发现cAMP- PKA 依赖性下调菌丝形态发生的主要抑制因子 Nrg1，与菌丝转录程序的启动相关。持续的菌丝转录需要将 Hda1 招募到菌丝特异性基因的启动子上，它导致启动子染色质的变化。我们建议确定 cAMP-PKA 依赖性 Nrg1 下调的机制和调节剂目标 1 中的菌丝诱导。目标 2 定义了宿主因子和白色念珠菌途径 Hda1 启动子招募及其在侵袭性念珠菌病中的重要性。目标 3 研究 Cph2的功能和调节。使用分子遗传学、细胞学的综合方法我们的学习将涉及生物学和生物化学。这项工作将为我们提供一个更好地了解白色念珠菌如何整合各种信号来控制生长和的发展，以及它如何在各种宿主环境中生存和发展。