Yeast cell wall damage response pathways

描述（由申请方提供）：白色念珠菌是美国第4大最常见的医院感染因子，在念珠菌血症患者中具有高死亡率。信号通路控制着对适应、生存和发病至关重要的过程。我们广泛的兴趣是了解信号通路在C。白色念珠菌的生存和发病机制。我们的目标是确定抗真菌药物对Psk 1-Sko 1细胞壁损伤反应的信号转导机制。用细胞壁合成抑制剂卡泊芬净治疗后，转录因子Sko 1的表达增加，卡泊芬净是一种最近获得许可的具有新靶点的抗真菌药物。这种增加依赖于蛋白激酶Psk 1，并随着细胞壁生物合成基因的上调而达到高潮。我们最近的研究结果表明，转录因子Rlm 1控制Sko 1表达细胞壁损伤。此外，我们发现含有质膜受体Hgt 9突变的菌株对卡泊芬净过敏。因此，我们的中心假设是，增加SKO 1的表达细胞壁损伤是由Psk 1磷酸化的转录因子Rlm 1，并通过质膜受体检测细胞壁扰动激活这一途径发生。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Rlm 1在Psk 1-Sko 1细胞壁损伤反应中的作用; 2）确定Psk 1-Sko 1细胞壁损伤反应中的上游信号组分。这个试验性的建议是创新的，在确定一个新的适应机制，细胞壁损伤，这是唯一的C。白色念珠菌此外，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剂。这项试点提案的资金将扩大约翰杰伊学院的研究，并将生物医学研究介绍给目前在这一关键领域缺乏机会的学生群体。 公共卫生相关性：白色念珠菌是人类的主要真菌病原体。C.仅在美国，白色念珠菌是第四大最常见的医院感染因子，在念珠菌血症患者中具有高死亡率。信号通路对于适应、生存和发病机制至关重要。这一建议是相关的，因为我们将确定控制抗真菌药物反应的信号机制。

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.