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: 10507563
• 负责人: Devesha Kulkarni
• 金额: $ 15.39万
• 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/10507563
• 关键词: Address; 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; 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; Pharmacology; Phenotype; Plasma; Plasminogen Activator Inhibitor 1; Principal Investigator; 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; macrophage; member; microbial; microbiota; monocyte; mouse model; non-alcoholic fatty liver disease; novel; 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.

项目总结