Microbial drivers of metabolically unhealthy obese phenotype

代谢不健康肥胖表型的微生物驱动因素

• 批准号: 10655650
• 负责人: Devesha Kulkarni
• 金额: $ 15.24万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655650
• 关键词: Adipose tissue; Affect; Antigens; Bioinformatics; Biology; Body Composition; Body Weight; Cells; Complement; Consumption; Data; Dendritic Cells; Development; Development Plans; Diet; Disease; Dyslipidemias; Ecology; Energy Metabolism; Enterobacteriaceae; Environment; Fatty acid glycerol esters; Flow Cytometry; Fostering; Gene Expression; Genetic; Glucose Intolerance; Goals; Goblet Cells; Gut Mucosa; Heterogeneity; Human; Immersion; Immune; Immune Tolerance; Immune system; Immunology; Individual; Infection; Infiltration; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intervention; Intestines; Knowledge; Lipids; Liver; Macrophage; Manuscripts; Measures; Mentored Research Scientist Development Award; Mentorship; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Methods; Microbe; Mission; Modeling; Mononuclear; Mucous Membrane; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Persons; Phagocytes; Phenotype; Plasma; Plasminogen Activator Inhibitor 1; Principal Investigator; Proliferating; Publishing; Quantitative Reverse Transcriptase PCR; RANTES; Reporter; Research; Research Personnel; Ribosomal RNA; Role; SERPINE1 gene; Seminal; Serum; Shotgun Sequencing; Source; Specimen; System; Techniques; Thinness; Training; Triglycerides; Universities; Washington; Weight Gain; Wild Type Mouse; bacterial community; career development; cytokine; dysbiosis; experience; gut microbes; gut microbiome; gut microbiota; host-microbe interactions; human subject; humanized mouse; improved; inflammatory marker; insulin sensitivity; member; microbial; microbiota; monocyte; mouse model; non-alcoholic fatty liver disease; novel; pharmacologic; photoactivation; post-doctoral training; programs; skills; stool sample; tool; trafficking; transcriptomics

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.

项目摘要 这项指导研究科学家发展奖的申请将促进主要研究者 （PI）向独立性的过渡，剖析了与肥胖相关的代谢疾病中宿主 - 微生物相互作用。 候选人：PI是一名实验生物学家，在肠粘膜免疫学方面具有很强的背景 感染生物学。她在粘膜Rodney Newberry博士的心态下进行了博士后培训 免疫学专家。在Newberry博士的指导下，PI展示了肠道杯细胞的新作用 促进对腔抗原的免疫耐受性。此外，PI还证明了如何进入 细菌与肠道杯细胞相互作用以调节其功能。她将利用在 她的训练以表征与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：PI将根据Newberry博士和博士的委托执行该建议。 塞缪尔·克莱因（Samuel Klein）（肥胖研究领域的领导者），由一个科学专家团队的建议 有培养独立研究人员的经验。华盛顿大学提供了一个杰出的环境， 将促进PI职业发展的合作者和核心。该提案建立在PI的先验基础上 经验并填补了培训的空白，为她提供了独立所需的工具。它包括 以下目标：（1）巨噬细胞生物学的主要技术（即免疫细胞运输，表型）； （2）发展肥胖和代谢功能障碍方面的专业知识； （3）微生物生态学的培训； （4）沉浸在 生物信息学； （5）与该提案直接相关的出版手稿。 研究计划：该提案的科学前提是，来自具有代谢的人的肠道菌群 与代谢健康的肥胖症（MHO）肠道和脂肪组织相比，不健康的肥胖症（MUO） 炎。为了研究微生物驱动因素对代谢综合征发作的作用，PI具有 建立了一种殖民的模型，以殖民地殖民相同相同的野生型小鼠食用正常的食物饮食 从特征良好的肥胖或代谢健康的瘦（MHL）人类受试者中收集的标本 已知的脂肪组织注射，葡萄糖肠道和全身胰岛素敏感性的已知程度。 初步研究表明，用MUO定居但没有MHO或MHL供体微生物群的小鼠具有 葡萄糖摄入剂，较高的血清胰岛素浓度和巨噬细胞的显着膨胀 肠道和脂肪组织。通过完成提议的目标，PI将解决1）是否肠道微生物是否来自 MUO患者促进宿主注射和代谢性疾病的发作，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贡献。在完成这些目标时， 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， 微生物生态学和代谢功能障碍成为一个独立研究者，其长期目标 与NIDDK任务保持一致，剖析微生物如何对肥胖相关的代谢疾病做出贡献。