Role of leptin in mucosal protection during Clostridium difficile infection

描述(由申请人提供)：艰难梭菌感染是主要的医疗负担。艰难梭菌感染的发病率持续上升，据美国疾病控制与预防中心估计，美国每年约有50万人感染艰难梭菌，艰难梭菌相关性腹泻每年导致美国14,000人死亡。此外，感染不再局限于卫生保健机构，最近的研究表明艰难梭菌感染也蔓延到社区。艰难梭菌感染每年给医疗保健系统造成的疾病负担估计至少为10亿美元。目前治疗艰难梭菌感染的标准是停止使用令人不快的抗生素，并使用不同的抗菌素来靶向细菌。然而，这些显然是不够的，因为有高死亡率和高复发率，因此我们需要更好地了解艰难梭菌结肠炎的发病机制，以设计新的治疗方法。 我们在艰难梭菌感染患者和艰难梭菌结肠炎小鼠模型中的初步研究表明，瘦素信号促进了早期炎症反应，从而增强了疾病，但也清除了病原体。我们现在建议使用艰难梭菌结肠炎的小鼠模型来确定导致瘦素作用的下游机制。我们将使用艰难梭菌结肠炎的小鼠模型来确定瘦素介导的炎症的节奏和特征，并确定负责瘦素介导的疾病增强和病原体清除的关键介质。这些研究将为瘦素在结肠炎症中的作用提供新的见解，并有可能为艰难梭菌感染的宿主指导治疗发现新的治疗靶点。这项建议利用了弗吉尼亚大学的机构承诺和培训环境、培养细胞培养实验室的资源以及艰难梭菌腹泻疾病研究领域的专家合作者和顾问的投入。 感染、肠道微生物组研究、瘦素生物学和免疫学。我的职业发展计划包括来自我的指导团队的结构化监督和指导，有针对性的课程工作，以获得项目关键领域(微生物发病机制，高级免疫学，生物统计学)的新技能，专注于研讨会，以提高教师发展技能，出版基准和申请独立资金的计划，所有这些都将帮助我成为艰难梭菌感染领域的独立研究员。

DESCRIPTION (provided by applicant): Clostridium difficile infections are a major healthcare burden. The incidence of C. difficile infections continues to rise and according to CDC estimates, approximately 500,000 people in U.S. are infected with C. difficile each year and C. difficile-associated diarrhea is the cause of 14,000 American deaths each year. Furthermore, the infections are no longer restricted to health care facilities, and recent studies indicate spred of C. difficile infection to the community as well. The annual burden of disease to the healthcare system due to C. difficile infections is estimated to be at least $1 billion. The current standard f care for C. difficile infections is stopping the offending antibiotic and use of different antibiotcs to target the bacterium. However, these are clearly inadequate since there is high mortality and high rates of recurrent infections, and thus we need to better understand the pathogenesis of C. difficile colitis to design newer therapeutic approaches. Our preliminary studies in patients with C. difficile infection and in a murine model of C. difficie colitis show that leptin signaling promotes an early inflammatory response that enhances disease but also clears pathogen. We now propose to identify the downstream mechanisms that are responsible for leptin actions, using a murine model of C. difficile colitis. We will use a mouse model of C. difficile colitis to determine the tempo and character of leptin-mediated inflammation and identify the critical mediators that are responsible for leptin- mediated disease enhancement and pathogen clearance. These studies will provide novel insights into the role of leptin in colonic inflammation and have the potential to uncover new therapeutic targets for possible host- directed treatments of C. difficile infections. This proposal leverages the institutional commitment and training environment at UVA, resources of the Petri Lab and inputs from expert collaborators and consultants in the fields of diarrheal disease research, C. difficile infections, gut microbiome studies, leptin biology and immunology. My career development plan includes structured oversight and guidance from my mentorship team, targeted coursework to acquire novel skills in key areas of the project (microbial pathogenesis, advanced immunology, biostatistics), focused workshops to enhance faculty development skills, publication benchmarks and plans to apply for independent funding, all of which will help establish me as an independent investigator in the field of C. difficile infections.