Intestinal Intelectin-1 regulation of obesity development

肠道 Intelectin-1 对肥胖发展的调节

• 批准号: 10739656
• 负责人: Juan D. Matute
• 金额: $ 17.41万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739656
• 关键词: Ablation; Acetates; Acetylation; Adult; Affect; American; Antibiotics; Atropine; Award; Bacteria; Binding; Bioinformatics; Biological; Birth; Childhood; Communities; Complement; Development; Development Plans; Diet; Eating; Ecology; Enteral; Epithelial Cells; Exposure to; Feces; Funding; Genetic; Genetic Polymorphism; Genetic Transcription; Germ-Free; Gnotobiotic; Goals; Grant; High Fat Diet; Human; Immunology; In Vitro; Infant; Inflammatory Bowel Diseases; Institution; Insulin Resistance; Intestines; Journals; K-Series Research Career Programs; Life; Measures; Medicine; Mentors; Mentorship; Metabolic; Metabolic syndrome; Metabolism; Metagenomics; Methods; Microbe; Microbiology; Mission; Modeling; Mucous Membrane; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Obesity; Oral Administration; Organism; Outcome; Parasympathetic Nervous System; Phenotype; Physicians; Pre-Clinical Model; Predisposition; Production; Protein Secretion; Proteins; Public Health; Regulation; Research; Research Personnel; Research Project Grants; Research Proposals; Risk Factors; Role; Scientist; Secure; Starch; Supplementation; Testing; Therapeutic; Training; Translational Research; Weaning; Weight; Weight Gain; Wild Type Mouse; Work; biomarker identification; career; career development; cohort; critical period; design; diet-induced obesity; early childhood; excessive weight gain; genetic risk factor; germ free condition; ghrelin; growth hormone releasing hexapeptide; gut microbiota; host microbiome; host microbiota; host-microbe interactions; in vivo; infancy; insight; interdisciplinary approach; intestinal epithelium; medical schools; metatranscriptomics; microbial; microbiome; microbiota; mouse model; neonatal period; novel; obesity development; obesity in children; obesity prevention; obesity risk; overexpression; pandemic disease; pharmacologic; prevent; rapid weight gain; response; skills; sleep health; transcriptomics; translational study

PROJECT SUMMARY/ABSTRACT This proposal describes a 4-year career mentored research project with the goal of defining the effects of intestinal Intelectin-1 (ITLN1) in microbial function and composition and its role in the genesis of obesity and early life weight gain. Successful completion of the research and training plan will enable the investigator to gain the skills necessary to secure independent funding and become an independent physician-scientist. The inves- tigator's long-term goal is to define how the host-microbiota interface modulates the risk of obesity early in life through multidisciplinary approaches and enable the design of preventative obesity strategies starting in the neonatal period. The research aims and career development plan will work towards mastery and independence in gnotobiology, gut anaerobic microbiology, and preclinical models of metabolism and proficiency in functional and bioinformatic analysis of the microbiota and translational research in early life. The primary co-mentors are Dr. Richard S. Blumberg – an expert in mucosal immunology and preclinical models to study gut-microbiota interactions – and Dr. Alessio Fasano – a leader in pediatric translational studies in the host-microbiome interface –at Mass General Brigham/Harvard Medical School. The collaborative and mentorship team comprises a local, multi-institutional group of experts in bioinformatics, intestinal microbial ecology, mucosal immunology, metabo- lism, and childhood obesity. The research proposal seeks to explore interactions between intestinal ITLN1 and microbes in the genesis of obesity. ITLN1 has been associated with obesity in humans, but the mechanism(s) behind(s) this association are unknown. The preliminary findings suggest that ITLN1 binds a particular subset of bacteria in vivo and modulates the metabolic activity of the microbiome. Furthermore, intestinal ITLN1 might protect against obesity in a microbiota-dependent manner. The overall hypothesis of this mentored research is that intestinal ITLN1 protects from obesity by modulating the metabolic activity of ITLN1-bound bacteria. In this proposal, we will use in vitro transcriptomic and phenotypic analysis of ITLN1-bound bacteria and bottom-up and bottom down microbiological approaches in conventional and gnotobiotic mice with and without ITLN1 to under- stand the effects of ITLN1 on intestinal microbes and seek to provide critical information about mechanisms by which ITLN1 in the intestine can influence the host-susceptibility to obesity. Furthermore, the applicant will ex- plore the translational implication of ITLN1 binding to microbes in infants with adequate and excessive weight gain during the first two years of life, as rapid weight gain in this critical window is associated with childhood obesity. Expected outcomes include direct evidence that loss of a single protein (ITLN1) in the intestinal epithe- lium leads to obesity and metabolic syndrome through its effects on the microbiota and the development of the investigator's expertise in the mechanistic study of the host-microbiota interface in obesity and translational stud- ies in early life. This career development award will set the stage for an independent research career focused on developing strategies to prevent and treat obesity targeting the host-microbiota interface in early life.

项目摘要/摘要 该建议描述了一个为期4年的职业指导研究项目，目的是定义 微生物功能和组成中的肠内染蛋白-1（ITLN1）及其在肥胖起源中的作用 早期体重增加。成功完成研究和培训计划将使研究人员能够获得 确保独立资金并成为独立的身体科学家所需的技能。调查 - Tigator的长期目标是定义宿主 - 微生物群的界面如何调节生命早期肥胖的风险 通过多学科的方法，并实现了从事预防性肥胖策略的设计 新生儿期。研究目标和职业发展计划将致力于掌握和独立 在gnotobiology，肠道厌氧微生物学以及代谢和功能熟练程度的临床前模型 以及对早期菌群和翻译研究的生物信息学分析。主要的副官是 Richard S. Blumberg博士 - 粘膜免疫学和临床前模型的专家 互动 - 和Alessio Fasano博士 - 宿主 - 微生物界界面小儿翻译研究的领导者 - 大规模的杨百翰/哈佛医学院。合作和精通团队包括一个本地， 生物信息学专家，肠道微生物生态学，粘膜免疫学，代理 - lism和童年的对象。研究建议旨在探索肠道ITLN1和 肥胖起源中的微生物。 ITLN1与人类的肥胖有关，但是机制 在此关联的背后是未知的。初步发现表明ITLN1结合了特定子集 细菌在体内并调节微生物组的代谢活性。此外，肠道ITLN1可能 以依赖微生物群的方式预防肥胖。这项重要的研究的总体假设是 肠道ITLN1通过调节ITLN1结合细菌的代谢活性来保护肥胖。在这个 提案，我们将使用ITLN1结合细菌和自下而上的体外转录组和表型分析以及 在有和没有ITLN1的常规和gnotobiotic小鼠中，底部的微生物方法下降 施加ITLN1对肠道微生物的影响，并寻求提供有关机制的关键信息 肠中的ITLN1可以影响肥胖的宿主敏感性。此外，申请人将 在体重超重且体重过度 在生命的头两年中，随着这个关键窗口中的快速体重增加与童年有关 肥胖。预期结果包括直接证据表明，肠上皮中单蛋白（ITLN1）的丧失 LIUM通过其对微生物群的影响和发展而导致肥胖和代谢综合征 研究者在观察和翻译研究方面的机械研究方面的专业知识 早期的IE。该职业发展奖将为以独立研究职业为重点 为了制定预防和治疗针对早期宿主微生物界面的肥胖症的策略。