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

项目摘要 代谢紊乱，如肥胖和2型糖尿病，是发病和死亡的主要原因之一 在世界范围内，流行率达到流行病的水平。在过去的十年中，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， 免疫和炎症途径对外周营养素利用率变化的反应。这种炎症在 下丘脑的特征在于下丘脑的常驻和浸润免疫细胞的积累， 下丘脑，如小胶质细胞和促炎性骨髓细胞。此外，与饮食有关 下丘脑的免疫激活先于外周组织和外显体重的代谢紊乱 增益，暗示早期发病的下丘脑炎症的病理生理学代谢功能障碍。更 最近的研究表明，环境扰动，如产妇营养不良和压力， 下丘脑发育，以产生下丘脑代谢控制的持久改变。虽然 这些母体因素影响下丘脑回路，控制食欲，进食和 代谢，免疫细胞在下丘脑编程中的作用，在这一关键时期的发展是 更少被理解。因此，本K 01申请的目的是确定母体肠道微生物群的作用- 衍生代谢物对下丘脑内免疫发育的影响，确定这些重编程 事件影响下丘脑对代谢的控制，并增加代谢紊乱的终身风险。我会 测试我的假设在三个具体目标，1）证明压力诱导的免疫编程通过母体肠道- 微生物群来源的短链脂肪酸（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）通过以下方法确定分子机制： 其中母体SCFA调节小胶质细胞的发育和下丘脑对代谢控制的破坏。作为 母体肠道微生物组是容易接近的，并且可以以非侵入性的方式进行操作， 这项工作可能揭示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博士正在马里兰州大学Tracy Bale博士的实验室接受培训 医学院。此K 01应用程序的职业发展目标是为博士提供受保护的时间。 Jasarevic培养他新兴的研究计划，并建立一个通往学术独立的道路。 因此，此K 01应用程序旨在（1）获得免疫学方面的技术和教学培训 和代谢使用我们的下丘脑失调的小鼠模型;（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中的早期免疫的知识 （3）加强教育和指导。

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.