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

基本信息

批准号：
9113497
负责人：
Rajat Madan
金额：
$ 17.61万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113497
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 Plans Diarrhea Disease Educational workshop Entamoeba histolytica Environment European Exhibits Funding Health 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 Mucins Mus Mutation Neutrophil Infiltration Nosocomial Infections Obese Mice 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 Teacher Professional Development 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 microbiome gut microbiota innovation insight leptin receptor microbial microbiome mortality mouse model neutrophil new therapeutic target novel novel therapeutic intervention nutrition pathogen prevent receptor expression response skills tool

项目摘要

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负担。艰难梭菌感染的发病率持续上升，根据 CDC 估计，美国每年约有 500,000 人感染艰难梭菌，艰难梭菌相关腹泻每年导致 14,000 美国人死亡。此外，感染不再局限于医疗机构，最近的研究表明艰难梭菌感染也在社区中传播。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有问题的抗生素并使用不同的抗生素来针对细菌。然而，这些显然是不够的，因为其死亡率高，复发感染率高，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。我们对艰难梭菌感染患者和艰难梭菌结肠炎鼠模型的初步研究表明，瘦素信号传导促进早期炎症反应，从而增强疾病但也清除病原体。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速度和特征，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定向治疗发现新的治疗靶点。该提案利用了 UVA 的机构承诺和培训环境、Petri 实验室的资源以及腹泻病研究、艰难梭菌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导师团队的结构化监督和指导、旨在获得项目关键领域（微生物发病机制、高级免疫学、生物统计学）新技能的有针对性的课程、旨在提高教师发展技能的重点研讨会、出版基准和应用计划获得独立资助，所有这些都将帮助我成为艰难梭菌感染领域的独立研究者。