Signal pathways controlling the bud to hypha transition

控制芽到菌丝转变的信号通路

• 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
• 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

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性感染的发病率。迫切需要 提高C.白色念珠菌，因为易感个体池 由于新的医疗手段、人口老龄化以及 耐药菌株的出现。C.白色念珠菌是它的生长能力 以不同的形态在宿主中传播。小的出芽细胞更容易 殖民美国大兵在血液中传播，而细长的菌丝细胞 介导侵入组织并促进生物膜形成。然而，目前的模型 约20年前开发的菌丝生长调节现在具有局限性。因此，我们认为， 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： 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。这些结果有望确定重要的新介质的菌丝 这一增长使该领域超越了对腺苷酸环化酶和cAMP信号传导的狭隘关注。目标二是 以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这一问题的认识上的空白。 刺激菌丝生长的机制，不能用以前的研究来解释， 集中于菌丝诱导基因的作用。目的3是确定影响菌丝生长的基因 通过研究在菌丝形成方面有缺陷的不寻常的临床分离株在宿主中的生长。这些 菌丝缺陷型临床菌株被认为是在菌丝生长过程中产生的，因为出芽细胞 能够更好地定殖胃肠道（而菌丝更好地侵入组织）。限定 调控菌丝形态发生转换的机制将为C. 白念珠菌的发病机制和发展抗真菌治疗的新机会。