Role of leptin in mucosal protection during Clostridium difficile infection

瘦素在艰难梭菌感染期间粘膜保护中的作用

• 批准号: 8767529
• 负责人: Rajat Madan
• 金额: --
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2014-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767529
• 关键词: Adipocytes; Adoptive Transfer; Adult; Amebic colitis; American; Antibiotics; Area; Bacteria; Benchmarking; Biological Markers; Biology; Biometry; Caring; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Chronic Bronchitis; Clinical; Clostridium difficile; Colitis; Colon; Communities; Data; Development; Development Plans; Diarrhea; Disease; Educational workshop; Entamoeba histolytica; Environment; European; Exhibits; Faculty; Funding; Health care facility; Healthcare; Healthcare Systems; Histology; Ileitis; Immune; Immune response; Immunology; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Injury; Intestines; Intoxication; Kinetics; Knowledge; LEPR gene; Length; Leptin; Liver; Mediating; Mediator of activation protein; Mentorship; Metabolism; Modeling; Mucins; Mus; Mutation; Neutrophil Infiltration; Nosocomial Infections; Obesity; Organism; Outcome; Pathogenesis; Patients; Phenotype; Predisposition; Public Health; Publications; Recurrence; Regulation; Research; Research Personnel; Resources; Risk; Role; STAT3 gene; Severities; Severity of illness; Signal Transduction; Structure; Symptoms; TLR4 gene; Testing; Therapeutic; Toxin; Training; Up-Regulation; antimicrobial peptide; bactericide; base; burden of illness; career development; chemokine; chemokine receptor; cytokine; db/db mouse; design; expectation; gut microbiota; innovation; insight; leptin receptor; mast cell; microbial; microbiome; mortality; mouse model; neutrophil; new therapeutic target; novel; novel therapeutic intervention; nutrition; pathogen; prevent; public health relevance; receptor expression; response; skills; tool

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.

描述（由申请人提供）：艰难梭菌感染是主要的医疗保健负担。艰难梭菌感染的发病率继续升高，根据CDC估计，美国约有500,000人每年感染了艰难梭菌，艰难梭菌相关的腹泻是每年14,000人死亡的原因。此外，感染不再限于医疗机构，最近的研究表明，艰难梭菌感染了社区。艰难梭菌感染引起的医疗保健系统的年度负担估计至少为10亿美元。艰难梭菌感染的当前标准F护理正在阻止有害的抗生素，并使用不同的抗生素来靶向细菌。但是，由于死亡率很高，复发性感染率很高，因此这些显然是不足的，因此我们需要更好地理解艰难梭菌结肠炎的发病机理，以设计更新的治疗方法。 我们在艰难梭菌感染患者以及艰难结肠炎菌的鼠模型中的初步研究表明，瘦素信号传导促进了早期的炎症反应，从而增强了疾病，但也可以清除病原体。现在，我们建议使用艰难梭菌结肠炎的鼠模型来确定负责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率的关键介质。这些研究将为瘦素在结肠炎症中的作用提供新颖的见解，并有可能发现新的治疗靶标，以造成艰难梭菌感染的可能宿主治疗。该建议利用UVA的机构承诺和培训环境，彼得里实验室的资源以及腹泻病研究领域的专家合作者和顾问的投入，艰难梭菌。 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我的指导团队的结构性监督和指导，针对课程，以在项目的关键领域（微生物发病机理，先进的免疫学，生物统计学）获得新技能，集中的研讨会，以增强教师的发展技能，出版物基准和计划，并计划申请独立的资金，所有这些都将在该领域中建立独立的研究员。