Signal pathways controlling the bud to hypha transition

控制芽到菌丝转变的信号通路

基本信息

批准号：
9752694
负责人：
James B Konopka
金额：
$ 32.45万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-07 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752694
关键词：
Adenylate Cyclase Antifungal Therapy Blood Circulation CRISPR/Cas technology Candida albicans Cells Chromosomes, Human, Pair 2 Clinical Cyclic AMP Data Defect Diploidy Disease Drug resistance Event Gastrointestinal tract structure Gene Expression Genes Genetic Genetic Screening Goals Grant Growth Heterogeneity Human Hyphae In Vitro Individual Infection Invaded Life Mediating Mediator of activation protein Medical Microbial Biofilms Modeling Morbidity - disease rate Morphogenesis Morphology Mucous Membrane Mutate Mutation Organism Partner in relationship Pathogenesis Pathway interactions Phosphoproteins Phosphorylation Phosphorylation Site Physiological Property Protein Kinase Proteins Regulation Role Serum Signal Pathway Signal Transduction Stimulus Systemic infection Therapeutic Time Tissues Transcriptional Regulation Virulence Work aging population cell growth regulation chromosome loss design experimental study genetic analysis genome sequencing gut colonization improved in vivo innovation insight mutant novel novel strategies novel therapeutics overexpression pathogenic fungus phosphoproteomics resistant strain

项目摘要

Project Summary: The human fungal pathogen Candida albicans causes a range of diseases including severe morbidity from mucosal infections and life-threatening systemic infections. There is an urgent need to improve the therapeutic management of C. albicans since the pool of susceptible individuals is increasing due to factors that include new medical treatments, an aging population, and the emergence of drug resistant strains. Central to the pathogenesis of C. albicans is its ability to grow in different morphologies that promote dissemination in the host. Small budding cells more readily colonize the G.I. tract and disseminate in the bloodstream, whereas elongated hyphal cells mediate invasion into tissues and promote biofilm formation. However, the current models for the regulation of hyphal growth that were developed ~20 years ago now have limitations. Therefore, we propose innovative new experiments to overcome the major barriers to progress. Aim 1 is to define the mechanisms of a novel cAMP-independent pathway for hyphal growth that we discovered recently. These results are expected to identify important new mediators of hyphal growth that move the field past the narrow focus on adenylyl cyclase and cAMP signaling. Aim 2 is to determine how phosphorylation regulates the signaling and morphogenesis proteins that promote hyphal formation. These studies are expected to fill a gap in our understanding of the mechanisms that stimulate hyphal growth that can’t be explained by previous studies that have focused on the role of hyphal-induced genes. Aim 3 is to determine which genes influence hyphal growth in the host by studying unusual clinical isolates that are defective in forming hyphae. These hyphal defective clinical strains are thought to arise during commensal growth, since budding cells are better able to colonize the GI tract (whereas hyphae are better invading into tissues). Defining the mechanisms that regulate the switch to hyphal morphogenesis will provide new insights into C. albicans pathogenesis and new opportunities for developing antifungal therapy.

项目概要：人类真菌病原体白色念珠菌引起一系列疾病，包括严重的粘膜感染和危及生命的全身感染的发病率迫切需要。改善白色念珠菌的治疗管理，因为易感个体库由于新的医疗方法、人口老龄化和耐药菌株的出现是白色念珠菌发病机制的核心是其生长能力。不同的形态，更容易促进小芽细胞在宿主中的传播。定植于胃肠道并在血流中传播，而细长的菌丝细胞介导对组织的侵袭并促进生物膜形成然而，目前的模型。大约 20 年前开发的菌丝生长调节现在已经存在局限性。我们创新地提出新的实验来克服进展的主要障碍。定义了一种新的不依赖 cAMP 的菌丝生长途径的机制最近发现的这些结果有望鉴定出重要的新菌丝介质。使该领域超越对腺苷酸环化酶和 cAMP 信号传导的狭隘关注的增长是目标 2。确定磷酸化如何调节信号传导和形态发生蛋白这些研究有望填补我们对菌丝形成的理解空白。以前的研究无法解释刺激菌丝生长的机制重点关注菌丝诱导基因的作用，目标 3 是确定哪些基因影响菌丝。通过研究在形成菌丝方面有缺陷的不寻常的临床分离株来观察宿主的生长。菌丝缺陷的临床菌株被认为是在共生生长过程中出现的，因为出芽细胞能够更好地定植胃肠道（而菌丝更容易侵入组织）。调节菌丝形态发生转换的机制将为 C. 白色念珠菌的发病机制和开发抗真菌治疗的新机遇。