Yeast cell wall damage response pathways

酵母细胞壁损伤反应途径

• 批准号: 7761039
• 负责人: Jason Malcolm Rauceo
• 金额: $ 15.55万
• 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/7761039
• 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; Gray unit of radiation dose; 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）：仅美国，白色念珠菌是美国第四大最常见的医院感染剂，念珠菌患者的死亡率很高。信号通路控制过程对于适应，生存和发病机理至关重要。我们的广泛兴趣是了解信号通路在白色念珠菌存活和发病机理中的作用。我们在此提案中的目标是确定PSK1-SKO1细胞壁损坏对抗真菌药物的损害反应的信号传导机制。转录因子SkO1的表达增加了用细胞壁合成抑制剂Caspofungin处理后，这是一种新近许可的抗真菌药物，具有新的靶标。这种增加取决于蛋白激酶PSK1，并与细胞壁生物合成基因的上调达到顶点。我们最近的发现表明，转录因子RLM1控制细胞壁损伤上的SKO1表达。同样，我们发现含有突变的质膜受体HGT9的菌株对Caspofungin高度敏感。因此，我们的中心假设是，在细胞壁损伤后的SkO1表达增加是由转录因子RLM1的PSK1磷酸化引起的，并且该途径的激活通过检测细胞壁扰动的质膜受体进行。为了检验我们的假设，我们提出了以下特定目的：1）确定转录因子RLM1在PSK1-SKO1细胞壁损伤响应中的作用； 2）确定PSK1-SKO1细胞壁损坏响应中的上游信号传导组件。该试点建议是在鉴定出对白色念珠菌独有的细胞壁损伤的新型自适应机制方面具有创新性的。此外，它将提高我们对新的抗真菌类别的反应的理解，这可能使我们能够预测抗药性机制并识别协同抑制剂。该试点建议的资金将扩大约翰·杰伊学院的研究，并将生物医学研究引入目前在这个关键领域缺乏机会的学生人群。 公共卫生相关性：白色念珠菌是人类的主要真菌病原体。白色念珠菌是仅美国的第四大最常见的医院感染剂，念珠菌患者的死亡率很高。信号通路对于适应，生存和发病机理至关重要。该提议很重要，因为我们将确定控制对抗真菌药物的反应的信号传导机制。