Microbial drivers of metabolically unhealthy obese phenotype

项目概要（来自主要K 01奖项） 本申请的指导研究科学家发展奖将有助于主要研究者 (Pl)的过渡到独立解剖宿主微生物在肥胖相关的代谢疾病的相互作用。 候选人：PI是一位实验生物学家，在肠道粘膜方面有很强的背景！免疫学和 感染生物学她做了她的博士后培训的指导下博士罗德尼纽贝里，粘膜 免疫学专家在纽贝里博士的指导下，Pl证明了肠杯状细胞的新作用 促进对管腔抗原的免疫耐受。此外，PI还证明了肠道如何 细菌与肠杯状细胞相互作用以调节它们的功能。她将利用在此期间获得的技能 她的训练，以表征肥胖相关的肠道微生物和肠道免疫细胞之间的对话。 职业发展计划：Pl将在纽贝里博士和罗琳博士的共同指导下执行此计划。 塞缪尔·克莱因（肥胖研究领域的领导者），由一组科学专家提出建议， 培养独立调查员的经验。华盛顿大学提供了一个出色的环境， 合作者和核心，将促进PL的职业发展。这一建议建立在Pl的先验基础上， 经验，并填补了她的培训空白，为她提供了独立所需的工具。它包括 以下目标：（1）掌握巨噬细胞生物学技术（即，免疫细胞运输、表型分析）; (2)发展肥胖和代谢功能障碍的专业知识;（3）微生物生态学培训;（4）沉浸在 生物信息学;（5）出版与本提案直接相关的手稿。 研究计划：该提案的科学前提是，来自代谢紊乱个体的肠道微生物群 与代谢健康肥胖（MHO）相比，不健康肥胖（MUO）推动肠和脂肪组织 炎症为了研究微生物驱动因素在代谢综合征发病中的作用，PI已经 建立了用粪便摄取正常食物的遗传上相同的野生型小鼠的定殖模型 从充分表征的肥胖或代谢健康的瘦型（MHL）人类受试者中采集的样本， 已知程度的脂肪组织炎症、葡萄糖耐受不良和全身胰岛素敏感性。 初步研究表明，用MUO而不是MHO或MHL供体微生物群定殖的小鼠， 葡萄糖耐受不良、血清胰岛素浓度升高和巨噬细胞显著扩增。 肠和脂肪组织。通过完成拟议的目标，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，2）确定 单核吞噬细胞在微生物群驱动的代谢功能障碍中的作用。为了实现这些目标， Pl将补充她在粘膜方面的专业知识！免疫学与巨噬细胞生物学的严格训练， 微生物生态学和代谢功能障碍，成为一个独立的研究者，长期目标是 剖析微生物如何导致肥胖相关的代谢疾病，与NIDDK的使命保持一致。

PROJECT SUMMARY (from main K01 award) This application for the Mentored Research Scientist Development Award will facilitate the principal investigator (Pl)'s transition to independence dissecting host-microbe interactions in obesity-related metabolic diseases. Candidate: The Pl is an experimental biologist with a strong background in gut mucosa! 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 Pl demonstrated the novel role of intestinal goblet cells in promoting immune tolerance to luminal antigens. Additionally, the Pl 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 Pl 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 Pl's career development. This proposal builds on the Pl'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 Pl 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 Pl 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 Pl will complement her expertise in mucosa! 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.