Signal pathways controlling the bud to hypha transition

控制芽到菌丝转变的信号通路

• 批准号: 10406353
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406353
• 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。有一个迫切的需要 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 emergence of drug resistant strains.白色念珠菌发病机制的核心是其生长能力 以不同的形态促进在宿主中的传播。小细胞更容易出芽 殖民美国大兵在血流中传播和传播，而细长的菌丝细胞 介导对组织的侵袭并促进生物膜的形成。 However, the current models for the 大约 20 年前开发的菌丝生长调节现在已经存在局限性。所以， 我们提出创新性的新实验来克服进展的主要障碍。目标 1 是 定义了一种新的独立于 cAMP 的菌丝生长途径的机制，我们 discovered recently.这些结果有望确定菌丝的重要新介质 使该领域超越对腺苷酸环化酶和 cAMP 信号传导的狭隘关注。目标 2 是 确定磷酸化如何调节信号传导和形态发生蛋白 promote hyphal formation.这些研究有望填补我们理解上的空白 以前的研究无法解释刺激菌丝生长的机制 focused on the role of hyphal-induced genes.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。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，因为出芽细胞 能够更好地定植胃肠道（而菌丝更容易侵入组织）。定义 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。

项目成果

An N-acetylglucosamine transporter required for arbuscular mycorrhizal symbioses in rice and maize.

• DOI: 10.1038/nplants.2017.73
• 发表时间: 2017-05-26
• 期刊: Nature plants
• 影响因子: 18
• 作者: Nadal M;Sawers R;Naseem S;Bassin B;Kulicke C;Sharman A;An G;An K;Ahern KR;Romag A;Brutnell TP;Gutjahr C;Geldner N;Roux C;Martinoia E;Konopka JB;Paszkowski U
• 通讯作者: Paszkowski U

N-Acetylglucosamine Metabolism Promotes Survival of Candida albicans in the Phagosome.

• DOI: 10.1128/msphere.00357-17
• 发表时间: 2017-09
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Vesely EM;Williams RB;Konopka JB;Lorenz MC
• 通讯作者: Lorenz MC

cAMP-independent signal pathways stimulate hyphal morphogenesis in Candida albicans.

• DOI: 10.1111/mmi.13588
• 发表时间: 2017-03
• 期刊: Molecular microbiology
• 影响因子: 3.6
• 作者: Parrino SM;Si H;Naseem S;Groudan K;Gardin J;Konopka JB
• 通讯作者: Konopka JB