Intestinal Intelectin-1 regulation of obesity development

项目摘要/摘要 这份提案描述了一个为期4年的职业指导研究项目，目标是确定 肠道内毒素-1(ITLN1)的微生物功能和组成及其在肥胖发生和发展中的作用 早年体重增加。研究和培训计划的成功完成将使调查员能够 获得独立资助并成为一名独立的内科科学家所需的技能。这些投资- Tigator的长期目标是定义宿主-微生物区系界面如何调节生命早期肥胖的风险 通过多学科的方法，并使预防肥胖战略的设计从 新生儿期。研究目标和职业发展计划将朝着精通和独立的方向发展 灵知生物学、肠道厌氧微生物学、新陈代谢的临床前模型和对功能的熟练程度 以及微生物区系的生物信息学分析和早期生命的翻译研究。主要的共同导师是 Richard S.Blumberg博士--研究肠道微生物区系的粘膜免疫学和临床前模型专家 相互作用-和Alessio Fasano博士-宿主-微生物组界面的儿科翻译研究的领导者 -在麻省总医院/哈佛医学院。协作和指导团队包括一名当地的， 生物信息学、肠道微生物生态学、粘膜免疫学、新陈代谢等方面的多机构专家小组 List和儿童肥胖症。该研究计划旨在探索肠道ITLN1和 微生物在肥胖发生中的作用。ITLN1与人类肥胖有关，但其机制(S) (S)这个联想的背后是不为人知的。初步研究结果表明，ITLN1结合了特定的子集 细菌在体内，并调节微生物组的代谢活动。此外，肠道ITLN1可能 以依赖微生物区系的方式预防肥胖。这项有指导的研究的总体假设是 肠道中的ITLN1通过调节与ITLN1结合的细菌的代谢活动来预防肥胖。在这 建议，我们将使用体外转录和表型分析ITLN1结合的细菌和自下而上和 自下而上的微生物学方法在具有和不具有ITLN1的常规和诺生菌小鼠中到Under- 了解ITLN1对肠道微生物的影响，并通过以下方式寻求提供有关机制的关键信息 肠道中的哪种ITLN1可以影响宿主对肥胖的易感性。此外，申请人将会- 适重和超重婴儿中ITLN1与微生物结合的翻译意义 在生命的头两年里体重迅速增加，因为在这一关键时期体重快速增加与童年有关 肥胖。预期结果包括直接证据表明，肠上皮中单一蛋白质(ITLN1)的丢失- 锂通过对微生物区系的影响导致肥胖和代谢综合征。 研究人员在肥胖和翻译研究中宿主-微生物区系界面的机制研究方面的专业知识- 我还处于早期生命阶段。这一职业发展奖将为专注于独立研究的职业生涯奠定基础 制定针对早期生活中宿主-微生物区系界面的预防和治疗肥胖症的策略。

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.