Role of leptin in mucosal protection during Clostridium difficile infection

描述（由申请方提供）：艰难梭菌感染是一种主要的医疗负担。C.艰难梭菌感染持续上升，根据CDC的估计，美国约有50万人感染了艰难梭菌。difficile和C.与艰难梭菌相关的腹泻是美国每年14,000例死亡的原因。此外，感染不再局限于卫生保健设施，最近的研究表明，C。也会影响到社区。由于C.艰难梭菌感染估计至少10亿美元。目前的标准f照顾C。艰难梭菌感染是停止进攻抗生素和使用不同的抗生素，以针对细菌。然而，这些显然是不够的，因为有高死亡率和高复发率的感染，因此，我们需要更好地了解C。设计新的治疗方法。 我们对C.艰难梭菌感染和小鼠模型中的C.表明瘦素信号促进早期炎症反应，增强疾病，但也清除病原体。我们现在建议使用C.艰难性结肠炎我们将使用C.艰难性结肠炎，以确定瘦素介导的炎症的克里思和特征，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，并有可能发现新的治疗靶点，用于可能的宿主定向治疗C。艰难感染。该提案充分利用了UVA的机构承诺和培训环境，Petri实验室的资源以及来自疟疾研究领域的专家合作者和顾问的投入，C。艰难 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导师团队的结构化监督和指导，有针对性的课程，以获得项目关键领域的新技能（微生物发病机理，高级免疫学，生物统计学），重点研讨会，以提高教师发展技能，出版基准和计划申请独立资助，所有这些都将有助于建立我作为一个独立的调查员在C领域。艰难感染。

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.