Yeast cell wall damage response pathways

酵母细胞壁损伤反应途径

• 批准号: 8214563
• 负责人: Jason Malcolm Rauceo
• 金额: $ 15.47万
• 依托单位: JOHN JAY COLLEGE OF CRIMINAL JUSTICE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214563
• 关键词: Adhesions; Anabolism; Antifungal Agents; Applications Grants; Area; Biomedical Research; Candida albicans; Candida glabrata; Caspofungin; Cell Wall; Cell membrane; Collaborations; Development; Epitopes; Event; Extramural Funding Mechanisms; Fostering; Funding; Funding Agency; Future; Gene Expression; Gene Targeting; Genes; Genetic Techniques; Human; Infectious Diseases Research; Licensing; Mediating; Membrane Proteins; Microbial Biofilms; Modeling; Molecular Genetics; Monitor; Mutation; Orthologous Gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phosphorylation; Pilot Projects; Population; Process; Protein Kinase; Proteins; Research; Role; Signal Pathway; Signal Transduction; Stress; Stress Response Signaling; Students; Testing; Therapeutic; Up-Regulation; Work; Yeast Model System; Yeasts; base; biological adaptation to stress; candidemia; career; college; cost; dimorphism; environmental change; genetic analysis; inhibitor/antagonist; innovation; interest; meetings; mortality; mutant; novel; pathogen; programs; public health relevance; receptor; resistance mechanism; response; transcription factor

DESCRIPTION (provided by applicant): Candida albicans is the 4th most common nosocomial infective agent in the US alone with a high mortality rate amongst candidemia patients. Signaling pathways control processes critical for adaptation, survival, and pathogenesis. Our broad interest is to understand the roles of signaling pathways in C. albicans survival and pathogenesis. Our objective in this proposal is to determine the signaling mechanism underlying the Psk1-Sko1 cell wall damage response to antifungal drugs. Expression of the transcription factor Sko1 is increased following treatment with the cell wall synthesis inhibitor caspofungin, a recently licensed antifungal drug with a novel target. This increase is dependent on protein kinase Psk1, and culminates with the upregulation of cell wall biosynthesis genes. Our most recent findings show that transcription factor Rlm1 controls Sko1 expression upon cell wall damage. Also, we found that strains containing mutations to the plasma membrane receptor Hgt9 are hypersensitive to caspofungin. Thus, our central hypothesis is that increased SKO1 expression following cell wall damage is caused by Psk1 phosphorylation of transcription factor Rlm1, and activation of this pathway occurs through plasma membrane receptors detecting cell wall perturbation. To test our hypothesis, we propose the following specific aims: 1) To determine the role of transcription factor Rlm1 in the Psk1-Sko1 cell wall damage response; and 2) To determine the upstream signaling components in the Psk1-Sko1 cell wall damage response. This pilot proposal is innovative in the identification of a novel adaptive mechanism to cell wall damage that is unique in C. albicans. Further, it will advance our understanding of the response to a new class of antifungal, which may allow us to anticipate resistance mechanisms and identify synergistic inhibitors. Funding of this pilot proposal will expand research at John Jay College and introduce biomedical research to a student population that currently lacks opportunities in this critical area. PUBLIC HEALTH RELEVANCE: Candida albicans is the major fungal pathogen of humans. C. albicans is the 4th most common nosocomial infective agent in the US alone with a high mortality rate amongst candidemia patients. Signaling pathways are critical for adaptation, survival, and pathogenesis. This proposal is relevant as we will determine the signaling mechanisms that govern the response to antifungal drugs.

描述(由申请人提供)：白色念珠菌是仅在美国最常见的医院感染性药物中的第四位，在念珠菌血症患者中死亡率很高。信号通路控制着对适应、生存和发病至关重要的过程。我们的兴趣是了解信号通路在白念珠菌存活和发病机制中的作用。我们在这项建议中的目标是确定Psk1-Sko1细胞壁损伤对抗真菌药物反应的信号机制。转录因子Sko1的表达在用细胞壁合成抑制剂Caspogenin治疗后增加，Caspogenin是一种最近获得批准的抗真菌药物，具有新的靶点。这种增加依赖于蛋白激酶Psk1，并随着细胞壁生物合成基因的上调而达到顶峰。我们最新的发现表明，转录因子Rlm1控制细胞壁损伤时Sko1的表达。此外，我们还发现含有质膜受体Hgt9突变的菌株对卡泊芬净过敏。因此，我们的中心假设是，细胞壁损伤后SKO1表达的增加是由转录因子Rlm1的Psk1磷酸化引起的，这一途径的激活是通过质膜受体检测细胞壁的扰动而发生的。为了验证我们的假设，我们提出了以下具体目标：1)确定转录因子Rlm1在Psk1-Sko1细胞壁损伤反应中的作用；2)确定Psk1-Sko1细胞壁损伤反应中的上游信号成分。这一试点方案在确定一种新的适应细胞壁损伤的机制方面具有创新性，这种机制在白念珠菌中是独一无二的。此外，它将促进我们对一类新的抗真菌药物的反应的理解，这可能使我们能够预测耐药机制并识别协同抑制药。这项试点提案的资金将扩大约翰·杰伊学院的研究，并向目前在这一关键领域缺乏机会的学生群体介绍生物医学研究。 公共卫生相关性：白色念珠菌是人类的主要真菌病原体。仅在美国，白色念珠菌就是第四种最常见的医院感染性细菌，在念珠菌血症患者中死亡率很高。信号通路在适应、生存和发病机制中起关键作用。这一建议是相关的，因为我们将确定管理抗真菌药物反应的信号机制。

项目成果

Genome-wide transcriptional profiling and enrichment mapping reveal divergent and conserved roles of Sko1 in the Candida albicans osmotic stress response.

• DOI: 10.1016/j.ygeno.2013.06.002
• 发表时间: 2013-10
• 期刊: GENOMICS
• 影响因子: 4.4
• 作者: Marotta, Dawn H.;Nantel, Andre;Sukala, Leonid;Teubl, Jennifer R.;Rauceo, Jason M.
• 通讯作者: Rauceo, Jason M.