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，是导致发病率和死亡率的主要原因之一。 世界范围内，流行率达到流行水平。在过去的十年里，临床前研究表明 下丘脑是大脑的一个区域，负责控制周围的葡萄糖、脂肪和能量代谢，激活 免疫和炎症途径对外周营养素可获得性变化的反应。这是一种炎症 下丘脑的特点是堆积的常驻和浸润性免疫细胞的 下丘脑，如小胶质细胞和促炎髓系细胞。此外，与饮食有关的 下丘脑的免疫激活先于外周组织和显性体重的代谢紊乱 Gain，在代谢功能障碍的病理生理学中牵涉到早期的下丘脑炎症。更多 最近的研究表明，环境扰动，如产妇营养不良和压力，会影响 下丘脑发育对下丘脑新陈代谢的控制产生持久的变化。虽然它是 众所周知，这些母性因素影响控制食欲、进食和营养的下丘脑回路。 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代谢 更少人理解。因此，这项K01应用的目标是确定母体肠道微生物区系的作用- 衍生代谢物对下丘脑内免疫发育的影响，决定了这些重新编程 这些事件会影响下丘脑对新陈代谢的控制，并增加代谢紊乱的终身风险。这就做 在三个具体目标上验证我的假设：1)通过母体肠道演示应激诱导的免疫程序- 微生物区系衍生的短链脂肪酸(SCFAs)，2)确定母体短链脂肪酸对 下丘脑对葡萄糖、脂肪和能量代谢的失调，3)通过以下方式确定分子机制 哪些母体SCFAs调节小胶质细胞的发育和下丘脑代谢控制的中断。AS 母体肠道微生物组很容易接触到，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新的战略和生物标志物的母亲逆境和持久的健康结果 后代。候选人埃尔丁·贾萨雷维奇博士正在马里兰大学特雷西·贝尔博士的实验室接受培训 医学院。这款K01应用程序的职业发展目标是为博士提供受保护的时间。 贾萨雷维奇培养他的新兴研究计划，并开辟一条学术独立的道路。 因此，K01应用程序的设计目的是(1)获得免疫学方面的技术和教学培训 并使用我们的下丘脑失调的小鼠模型进行代谢；(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，以 在中枢调节领域扩大我们对发育中的下丘脑早期免疫的认识 新陈代谢；以及(3)加强恩赐精神和指导。

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.