TWO-COMPONENT SIGNAL PROTEINS OF ASPERGILLUS FUMIGATUS

描述：这是Fogarty-NIH的一项提案，旨在为一项关于 来自人类致病真菌的双组分信号转导蛋白， 烟曲霉。家长奖助金的名称是“响应监管者 白念珠菌CaSSK1基因，1R01A147047-01。这项研究将是 在Calderone博士(PI)和Latge博士(国外)的实验室进行 合作者)。拉奇博士的实验室为我们的研究做出了许多贡献 从生化和病理两方面认识曲霉病的发病机制 分子方法。卡尔德龙博士的实验室将他们的研究重点放在 2组分组氨酸激酶及其反应调节信号蛋白 白色念珠菌。他已经证明了这些蛋白质(Chk1p和Csk1p)是 菌丝的形成和菌丝细胞的调节所必需的 表面蛋白。编码基因缺失的菌株也是无毒的。 这项研究的长期目标是确定 这些蛋白质与烟曲霉的生长和毒力有关。的假说 这一建议是，对这种有机体的生长和毒力的调节是 通过双分量信令实现。在其他系统中，双分量信令 是表达多种毒力因子所必需的。因此，对 这种有机体中的信号通路可能揭示更多关于毒力因子的信息 构建一株具有单基因干扰的菌株。的具体目标 这些建议包括：1)编码白念珠菌Chk1p同源基因 和Cssk1p进行克隆和鉴定。2)烟曲霉菌株 在这些基因中删除的每一个都将被构建和它们的表型 在体外表现出来的特征。3)基因缺失的菌株将在 小鼠侵袭性曲霉病鼻腔模型的建立。如果被确定为 对这种有机体来说很重要，我们的研究可能表明两组分蛋白质 是广谱抗真菌药物开发的相关靶点。

DESCRIPTION: This is a Fogarty-NIH proposal which seeks funding for a study of two-component signal transduction proteins from the human pathogenic fungus, Aspergillus fumigatus. The parent grant is entitled, "The response regulator gene (CaSSK1) of Candida albicans, 1 R0l A147047-01. The study will be performed in the laboratories of Drs. Calderone (PI) and Latge (foreign collaborator). Dr. Latge's lab has made numerous contributions to our understanding of the pathogenesis of aspergillosis through both biochemical and molecular approaches. Dr. Calderone's lab has focused their research on the 2-component histidine kinases and the response regulator signal proteins of Candida albicans. He has shown that these proteins (Chk1p and Csk1p) are required for the formation of hyphae and the regulation of a hyphal cell surface protein. Strains deleted in their encoding genes are also avirulent. The long-term objective of this research is to establish the importance of these proteins in the growth and virulence of A. fumigatus. The hypothesis of this proposal is that regulation of growth and virulence in this organism is achieved through 2-component signaling. In other systems, 2-component signaling is required for the expression of multiple virulence factors. Thus, studies of signal pathways in this organism may reveal more about virulence factors than construction of a strain with a single-gene disruption. The specific aims of the proposal include: 1) genes encoding the homologs of the C. albicans Chk1p and Cssk1p are to be cloned and characterized. 2) Strains of A. fumigatus deleted in each of these genes will be constructed and their phenotypes characterized in vitro. 3) The gene deleted strains will be evaluated in an intranasal model of murine invasive aspergillosis. If determined to be important to this organism, our studies may suggest that 2-component proteins are relevant targets for the development of broad-spectrum antifungals.