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.

项目摘要代谢性疾病，例如肥胖和2型糖尿病，是发病率和死亡率的主要原因之一全球，患病率达到流行水平。在过去的十年中，临床前研究表明下丘脑是一种控制外周葡萄糖，脂肪和能量代谢的大脑区域免疫和炎症途径响应外周养分可用性的转移。这种炎症下丘脑的特征是居民的积累和浸润的免疫细胞的积累下丘脑，例如小胶质细胞和促炎性髓样细胞。此外，与饮食有关下丘脑的免疫激活先于周围组织中的代谢障碍和明显的重量增益，暗示下丘脑炎症早期在代谢功能障碍的病理生理学中。更多的最近的工作表明，环境扰动（例如母体营养不良和压力）会影响下丘脑的发育可在代谢的下丘脑控制中产生持久的改变。虽然是良好的表明这些母体因素会影响控制食欲，喂养和的下丘脑电路代谢，免疫细胞在下丘脑编程中的作用是不了解。因此，该K01应用的目的是确定母体肠道菌群的作用下丘脑内免疫发育的代谢产物，确定这些重新编程的方式事件会影响下丘脑对代谢的控制，并增加代谢疾病的终身风险。我会在三个特定目标中检验我的假设，1）表明母体肠道的压力诱导的免疫编程微生物群衍生的短链脂肪酸（SCFA），2）确定母体SCFA对葡萄糖，脂肪和能量代谢的下丘脑失调，3）确定分子机制哪种母体SCFA调节小胶质细胞的发展和下丘脑代谢控制的破坏。作为孕产妇的肠道微生物组很容易访问，并且可以以非侵入性方式进行操作，完成这项工作可能揭示了孕产妇逆境的新颖策略和生物标志物，并持久后代。候选人Eldin Jasarevic博士正在马里兰大学的Tracy Bale博士实验室进行培训医学院。该K01应用程序的职业发展目标是为Dr.提供受保护的时间。杰萨维奇（Jasarevic）培养他的新兴研究计划，并为学术独立迈进。因此，该K01的应用已设计为（1）获得免疫学方面的技术和教学培训使用下丘脑失调的小鼠模型的新陈代谢；（2）杠杆尖端技术，例如荧光激活的细胞分选，细胞类型特异性转基因和下一代测序，扩大我们对中央监管领域发展下丘脑早期免疫力的知识代谢；（3）增强赠款和指导。