Signal pathways controlling the bud to hypha transition

控制芽到菌丝转变的信号通路

• 批准号: 9912167
• 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
• 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/9912167
• 关键词: Adenylate Cyclase; Antifungal Therapy; Blood Circulation; CRISPR/Cas technology; Candida albicans; Cells; Chromosome 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

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.

项目总结： 人类真菌病原体白色念珠菌导致一系列疾病，包括严重的 黏膜感染和危及生命的系统性感染的发病率。有一个迫切的需要 改善对白色念珠菌的治疗管理，因为易感人群池 由于包括新的治疗方法、人口老龄化和 出现耐药菌株。白念珠菌致病的核心是它的生长能力 以不同的形态促进在宿主中的传播。更容易萌发的小细胞 定植于胃肠道并在血液中扩散，而细长的菌丝细胞 介导对组织的侵袭，促进生物膜的形成。然而，目前用于 大约20年前发展起来的菌丝生长调控现在有了局限性。因此， 我们提出了创新的新实验，以克服取得进展的主要障碍。目标1是 确定一种新的cAMP非依赖的菌丝生长途径的机制 最近发现的。这些结果有望确定重要的菌丝新介体。 生长使这个领域超越了对腺苷环化酶和cAMP信号的狭隘关注。目标2是 确定磷酸化如何调节信号和形态发生蛋白 促进菌丝形成。这些研究有望填补我们对 刺激菌丝生长的机制，以前的研究无法解释这些机制 重点阐述了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，在宿主中生长。这些 菌丝缺陷的临床菌株被认为是在共生生长过程中出现的，因为萌发的细胞 能够更好地在胃肠道定植(而菌丝更好地侵入组织)。定义 调节向菌丝形态发生转变的机制将为研究C. 白念珠菌的发病机制和发展抗真菌治疗的新机遇。