近平滑念珠菌钙调磷酸酶介导的逆境通路耐受棘白菌素的研究

项目名称： 近平滑念珠菌钙调磷酸酶介导的逆境通路耐受棘白菌素的研究

项目编号： No.81501784

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 赛思翔

作者单位： 滨州医学院

项目金额： 18万元

中文摘要： 近平滑念珠菌是与白色念珠菌在亲缘关系上较为接近的条件致病性真菌，并且与白色念珠菌同属CTG clade。真菌中，钙调磷酸酶介导的逆境通路调控致病及耐药相关功能，但在在白色念珠菌属中，该通路的功能发生显著的物种差异。近平滑念珠菌对棘白菌素有极强的耐药性，从而使治疗变得相当棘手。因而本项目以揭示近平滑念珠菌中钙调磷酸酶通路调控耐药基因的分子机制为目标，结合白色念珠菌属钙调磷酸酶逆境通路研究领域的最新成果，重点阐述1）Hsp90调控钙调磷酸酶响应棘白菌素分子机制; 2) 近平滑念珠菌中钙调磷酸酶调控的逆境通路的功能及其结构; 3）钙调磷酸酶介导的逆境通路调控靶基因表达的分子机制。最终为开发新型的抗真菌药物提供策略。

中文关键词： 白色念珠菌；进平滑念珠菌；钙调磷酸酶逆境通路；Hsp90分子伴侣；棘白菌素

英文摘要： Candida species (members of Ascomycota) are found as part of normal microflora of human mucosal surfaces, although sometimes they can cause vaginitis, oropharyngeal infections, and thrush, urogenital tract infections by invading the host through multiple ways, such as the urogenital tract, lungs and other mucosal surfaces. Candida infections excluded those on the skin and mucous membranes are referred to as invasive candidiasis, which includes candidemia, hematogenously disseminated candidiasis and infection of a single deep organ. A majority of these infections are due to bloodstream invasion and hematogenous spread. Over the last three decades, the frequency of candidemia among hospitalized patients has doubled. 17 Candida species has been identified to cause bloodstream infections. Among these 90% of infections can be attributed to five species: Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, and Candida krusei. Candida species are the fourth most common cause of nosocomial bloodstream infection and the third most common cause of bloodstream infection...As relatives of C. albicans in CTG clade, C. parapsilosis shares some common stress response pathways with C. albicans instead of compromised biofilm formation and disability of hyphae growth. Intriguingly, C. parapsilosis isolates highly resistant to echinocandins cause the difficulties in treatment. In Candida species, calcineurin-mediated stress response pathway involves in pathogenicity and drug-tolerance. In order to determine the mechanism of calcineurin-mediated stress response in drug-tolerance in C. parapsilosis, we are planning to perform the research in calcineurin-mediated stress response in C. parapsilosis by molecular approaches and bioinformatics technology. This research aims is to reveal 1) the role of Hsp90 in regulation calcineurin in response to echinocandins in C. parapsilosis. 2) stuctutre and components involve in the calcineurin stress pathway in C. parapsilosis. 3) the mechanism of calcineurin-mediated stress pathways in echinocandin tolerance. Eventually this research will provide strategies for the development of novel antifungal drugs.

英文关键词： C. albicans;C. parapsilosis ;calcineurin stress pathway ;Hsp90;echinocandins