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

• 批准号: 10442067
• 负责人: Eldin Jasarevic
• 金额: $ 10.2万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 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/10442067
• 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

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.

项目概要 肥胖和 2 型糖尿病等代谢紊乱是发病和死亡的主要原因之一 在世界范围内，患病率已达到流行病水平。过去十年中，临床前研究表明 下丘脑是一个控制外周葡萄糖、脂肪和能量代谢的大脑区域，它激活 免疫和炎症途径响应外周营养可用性的变化。这种炎症在 下丘脑的特点是常驻和浸润免疫细胞的积累 下丘脑，分别例如小胶质细胞和促炎性骨髓细胞。另外，与饮食有关 下丘脑的免疫激活先于周围组织的代谢紊乱和明显的体重 增益，暗示代谢功能障碍的病理生理学中下丘脑炎症的早期发作。更多的 最近的工作表明，环境扰动，例如孕产妇营养不良和压力，会影响 下丘脑的发育使下丘脑对新陈代谢的控制产生持久的改变。虽然它是 众所周知，这些母体因素会影响控制食欲、进食和进食的下丘脑回路。 新陈代谢，在这个发育的关键时期，免疫细胞在下丘脑编程中的作用是 不太了解。因此，K01 应用的目的是确定母体肠道微生物群的作用 下丘脑内免疫发育的衍生代谢物，决定了这些重编程的方式 事件影响下丘脑对代谢的控制，并增加终生代谢紊乱的风险。我会 在三个具体目标中检验我的假设，1）证明母体肠道应激诱导的免疫编程 微生物群衍生的短链脂肪酸 (SCFA)，2) 确定母体 SCFA 对身体的持久影响 下丘脑葡萄糖、脂肪和能量代谢失调，3) 通过以下方式确定分子机制 母体 SCFA 调节小胶质细胞发育并破坏下丘脑代谢控制。作为 母体肠道微生物组很容易获取，并且可以以非侵入性方式进行操作，完成 这项工作可能会揭示孕产妇逆境和持久健康结果的新策略和生物标志物 后代。候选人 Eldin Jasarevic 博士正在马里兰大学 Tracy Bale 博士的实验室接受培训 医学院。此 K01 申请的职业发展目标是为博士提供受保护的时间。 Jasarevic 致力于培养他的新兴研究项目并开辟一条走向学术独立的道路。 因此，此 K01 应用程序旨在 (1) 获得免疫学方面的技术和教学培训 使用我们的下丘脑失调小鼠模型进行新陈代谢； (2)利用尖端技术， 例如荧光激活细胞分选、细胞类型特异性转基因和下一代测序 扩展我们对中枢调节领域内发育中的下丘脑的早期免疫的了解 新陈代谢； (3) 加强资助和指导。