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Immune and developmental actions of the maternal microbial metabolites on the hypothalamus

母体微生物代谢物对下丘脑的免疫和发育作用

基本信息

批准号：
10374886
负责人：
Eldin Jasarevic
金额：
$ 14.62万
依托单位：
MAGEE-WOMEN'S RES INST AND FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374886
关键词：
Adult Anabolism Antiinflammatory Effect Applications Grants Behavioral Bioinformatics Biological Assay Blood Circulation Body Weight Brain Brain region Cell Separation Cells Clinical Data Desire for food Development Developmental Process Diet Dietary Fiber Embryo Energy Metabolism Epidemic Event Exhibits Expenditure Exposure to Feeding behaviors Female Fermentation Fetal Reduction Flow Cytometry Fluorescence-Activated Cell Sorting Functional disorder Gene Expression Gene Expression Profile Genes Genomics Goals Growth Health High Fat Diet Histone Deacetylase Inhibitor Homeostasis Hyperphagia Hypothalamic structure Immune Immunity Immunocompetent Immunology Infection Inflammation Inflammatory Insulin Knowledge Life Link Longevity Malnutrition Maryland Mentorship Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Microglia Mitochondria Modeling Molecular Morbidity - disease rate Myeloid Cells Neuroendocrinology Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Outcome Pathway interactions Peripheral Pharmacology Phenotype Population Predisposition Pregnancy Prevalence Production Property Regulation Research Risk Role Signal Transduction Source Stress Techniques Testing Time Tissues Training Training Support Transgenic Organisms Tumor-infiltrating immune cells United States National Institutes of Health Universities Vitamins Volatile Fatty Acids Weight Weight Gain Work Yolk Sac career development cell type critical period cytokine design dietary disorder risk early onset feeding fetal fetal programming glucose metabolism gut microbiome gut microbiota immune activation lipid metabolism male maternal microbiome maternal microbiota maternal stress medical schools metabolic phenotype metabolomics microbial microbiome microbiota microbiota metabolites monocyte mortality mother nutrition mouse model next generation sequencing novel novel marker novel strategies offspring paraventricular nucleus pre-clinical preclinical study prenatal prenatal stress progenitor programs recruit response sex success trafficking transcriptome transcriptome sequencing

项目摘要

Project Summary Metabolic disorders, such as obesity and type 2 diabetes, are one of the leading causes of morbidity and mortality worldwide, with prevalence reaching epidemic levels. Over the last decade, preclinical studies have shown that the hypothalamus, a brain region that exerts control over peripheral glucose, fat and energy metabolism, activate immune and inflammatory pathways in response to shifts in peripheral nutrient availability. This inflammation in the hypothalamus is characterized by the accumulation of resident and infiltrating immune cells of the hypothalamus, such as microglia and proinflammatory myeloid cells, respectively. Further, dietary-related immune activation of the hypothalamus precedes metabolic disturbances in peripheral tissues and overt weight gain, implicating early onset of hypothalamic inflammation in the pathophysiology of metabolic dysfunction. More recent work has shown that environmental perturbations, such as maternal malnutrition and stress, influence hypothalamic development to produce lasting alterations in the hypothalamic control of metabolism. While it is well-established that these maternal factors influence hypothalamic circuits that control appetite, feeding and metabolism, the role of immune cells in hypothalamic programming during this critical period of development is less understood. Thus, the objective of this K01 application is to determine the role of maternal gut microbiota- derived metabolites on immune development within the hypothalamus, determine how these reprogrammatic events influence hypothalamic control over metabolism, and increased lifelong risk for metabolic disorders. I will test my hypothesis in three Specific Aims, 1) demonstrate stress-induced immune programming by maternal gut- microbiota derived short chain fatty acids (SCFAs), 2) determine lasting impact of maternal SCFAs on hypothalamic dysregulation of glucose, fat, and energy metabolism, 3) identify the molecular mechanisms by which maternal SCFAs regulate microglia development and disruption of hypothalamic control of metabolism. As the maternal gut microbiome is readily accessible and can be manipulated in a non-invasive manner, completing this work may reveal novel strategies and biomarkers of maternal adversity and lasting health outcomes in offspring. The candidate, Dr. Eldin Jasarevic, is training in the lab of Dr. Tracy Bale at the University of Maryland School of Medicine. The career development goal of this K01 application is to provide protected time for Dr. Jasarevic to cultivate his emerging research program and forge a path towards academic independence. Accordingly, this K01 application has been designed to (1) gain technical and didactic training in immunology and metabolism using our mouse model of hypothalamic dysregulation; (2) leverage cutting-edge techniques, such as fluorescence activated cell sorting, cell-type specific transgenics and next generation sequencing, to expand our knowledge on early-life immunity in the developing hypothalamus within the field of central regulation of metabolism; and (3) enhance grantsmanship and mentorship.

项目总结