TWO-COMPONENT SIGNAL PROTEINS OF ASPERGILLUS FUMIGATUS

描述：这是Fogarty-NIH的一项提案，旨在为以下研究寻求资金： 来自人类病原真菌的双组分信号转导蛋白， 烟曲霉家长补助金的题目是"反应调节器 白色念珠菌的CaSSK1基因，1R01A147047 - 01。本研究将 在Calderone博士（PI）和Latge博士（国外）的实验室进行 合作者）。Latge博士的实验室为我们的 从生化和免疫两方面了解曲霉病的发病机制， 分子方法卡尔德龙博士的实验室将研究重点放在 2-组分组氨酸激酶和应答调节信号蛋白 白念珠菌他已经表明，这些蛋白质（Chk1p和Csk1p） 菌丝形成和菌丝细胞调节所需的 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 这些蛋白在A.烟熏。的假设 这一建议是，这种生物的生长和毒力的调节， 通过2分量信令实现。在其他系统中，2分量信令 是多种毒力因子表达所必需的。因此，研究 这种微生物中的信号通路可能揭示更多的毒力因子， 构建具有单基因破坏的菌株。的具体目标 该方案包括：1）编码C.白色念珠菌Chk1p 和Cssk1p的克隆和表征。2)株供试菌烟曲霉 将构建在这些基因中的每一个中缺失的表型， 在体外进行表征。3)基因缺失菌株将在 小鼠侵袭性曲霉病鼻内模型。如果确定是 重要的是，我们的研究可能表明，双组分蛋白质 是开发广谱抗真菌药的相关靶标。

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.