Microbial drivers of metabolically unhealthy obese phenotype

项目总结 申请导师研究科学家发展奖将促进首席研究人员 (PI)S向独立的转变剖析肥胖相关代谢性疾病中宿主与微生物的相互作用。 应聘者：PI是一名实验生物学家，在肠道粘膜免疫学和 感染生物学。她在罗德尼·纽伯里博士的指导下进行了博士后培训，罗德尼·纽伯里是一名黏膜医生 免疫学专家。在纽伯里博士的指导下，PI展示了肠道杯状细胞的新作用 在促进对管腔抗原的免疫耐受方面。此外，私家侦探还展示了肠道 细菌与肠道杯状细胞相互作用，调节它们的功能。她将利用在培训期间学到的技能 她接受的培训描述了肥胖相关肠道微生物和肠道免疫细胞之间的对话。 职业发展计划：PI将在Newberry博士和Dr.Newberry的共同指导下执行这项提议。 Samuel Klein(肥胖研究领域的领导者)，建议由一个科学专家团队提供建议，该团队也 培养独立调查人员的经验。华盛顿大学提供了一个出色的环境， 合作者和核心，将促进PI的职业发展。这项建议是建立在私家侦探之前的 经验，并填补了她在培训中的空白，为她提供了独立所需的工具。它包括 目标如下：(1)掌握巨噬细胞生物学技术(即免疫细胞运输、表型)； (2)培养肥胖和代谢功能障碍方面的专门知识；(3)微生物生态学方面的培训；(4)沉浸在 生物信息学；(5)发表与该提案直接相关的稿件。 研究计划：该提案的科学前提是来自具有新陈代谢的个体的肠道微生物群 不健康肥胖(MUO)与代谢健康肥胖(MHO)相比推动肠道和脂肪组织 发炎。为了研究微生物驱动因素在代谢综合征发病中的作用，PI 建立了一种用粪便进食普通食物的野生型小鼠的定植模型 样本收集自具有良好特征的肥胖或代谢健康的瘦肉型(MHL)受试者 已知程度的脂肪组织炎症、葡萄糖耐量和全身胰岛素敏感性。 初步研究表明，感染MUO的小鼠，而不是MHO或MHL捐赠者的微生物群 糖耐量异常、血清胰岛素浓度升高和巨噬细胞显著扩张 肠道和脂肪组织。通过完成提议的目标，PI将解决1)肠道微生物是否来自 MUO患者促进宿主炎症和代谢性疾病的发生，以及2)决定 单核吞噬细胞在微生物区系驱动的代谢功能障碍中的作用。为了实现这些目标， PI将通过严格的巨噬细胞生物学培训来补充她在粘膜免疫学方面的专业知识， 微生物生态和代谢功能障碍将成为独立的调查者，其长期目标是 根据NIDDK的任务，剖析微生物如何对肥胖相关的代谢性疾病做出贡献。

PROJECT SUMMARY This application for the Mentored Research Scientist Development Award will facilitate the principal investigator (PI)’s transition to independence dissecting host-microbe interactions in obesity-related metabolic diseases. Candidate: The PI is an experimental biologist with a strong background in gut mucosal immunology and infection biology. She did her postdoctoral training under the mentorship of Dr. Rodney Newberry, a mucosal immunology expert. Under Dr. Newberry’s guidance, the PI demonstrated the novel role of intestinal goblet cells in promoting immune tolerance to luminal antigens. Additionally, the PI has also demonstrated how enteric bacteria interact with intestinal goblet cells to modulate their function. She will leverage the skills gained during her training to characterize the dialogue between obesity-associated gut microbes and intestinal immune cells. Career Development Plan: The PI will execute this proposal under the co-mentorship of Dr. Newberry and Dr. Samuel Klein (a leader in the field of obesity research), advised by a team of scientific experts who also have experience in nurturing independent investigators. Washington University provides an outstanding environment, collaborators and cores that will foster the PI’s career development. This proposal builds on the PI’s prior experience and fills in the gaps in her training, providing her with the tools needed for independence. It includes the following objectives: (1) master techniques in macrophage biology (i.e., immune cell trafficking, phenotyping); (2) developing expertise in obesity and metabolic dysfunction; (3) training in microbial ecology; (4) immersion in bioinformatics; and (5) publishing manuscripts directly related to this proposal. Research Plan: The scientific premise of the proposal is that gut microbiota from individuals with metabolically unhealthy obesity (MUO) compared to metabolically healthy obesity (MHO) propel intestinal and adipose tissue inflammation. To investigate the role of microbial drivers on the onset of metabolic syndrome, the PI has established a model of colonizing genetically identical wildtype mice consuming a normal chow diet with stool specimens collected from well-characterized obese or metabolically-healthy lean (MHL) human subjects with known degrees of adipose tissue inflammation, glucose intolerance and whole-body insulin sensitivity. Preliminary studies demonstrate that mice colonized with MUO, but not MHO or MHL donor microbiota have glucose intolerance, higher serum insulin concentration and significant expansion of macrophages in the intestine and adipose tissue. By completing the proposed aims, the PI will address 1) whether gut microbes from people with MUO promote host inflammation and the onset of metabolic diseases, and 2) determine the contribution of monocuclear phagocytes in microbiota driven-metabolic dysfunction. In completing these aims, the PI will complement her expertise in mucosal immunology with rigorous training in macrophage biology, microbial ecology and metabolic dysfunction to becomes an independent investigator with the long-term goal of dissecting how microbes contribute to obesity-related metabolic disease, in alignment with the NIDDK mission.