Project I- Impact of Hypoxia-Ischemia and/or Inflammation on Microglia in Cerebellum

项目 I- 缺氧缺血和/或炎症对小脑小胶质细胞的影响

• 批准号: 9979920
• 负责人: MARGARET M. MCCARTHY
• 金额: $ 25.65万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-17 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979920
• 关键词: 3-Dimensional; Address; Antibiotics; Aromatase; Behavior; Behavioral; Birth; Brain; Brain Hypoxia-Ischemia; Brain region; Ceftriaxone; Cell Count; Cells; Cellular Stress; Cerebellar Nuclei; Cerebellar vermis structure; Cerebellum; Choline; Data; Development; Dinoprostone; Disease; Drops; Enzymes; Estradiol; Estrogen Receptors; Female; Glutamate Transporter; Golgi Apparatus; Health; Histologic; Human; Hypoxia; Hypoxic-Ischemic Brain Injury; Immune; Impaired cognition; Infant; Inflammation; Inflammatory; Injury; Label; Lipids; Membrane Lipids; Membrane Microdomains; Metabolism; Microglia; Minocycline; Morphology; Motor; Neurons; Perinatal Hypoxia; Phagocytes; Phagocytosis; Phosphatidylserines; Play; Production; Prostaglandin Production; Rattus; Recovery; Risk; Role; Sex Differences; Signal Transduction; Source; Surveys; Tetracyclines; Therapeutic; Time; Treatment Efficacy; Trees; base; dietary supplements; experimental study; granule cell; inhibitor/antagonist; injury recovery; insight; male; morphometry; natural hypothermia; neonatal hypoxic-ischemic brain injury; neurodevelopmental effect; neuron development; neuronal growth; novel; postnatal; protective effect; pup; receptor expression; reconstruction; synaptogenesis; therapeutic target

PROJECT SUMMARY: Sensitive periods in neuronal development vary by brain region, sensitivity and vulnerability to disruptive agents. We have discovered that the second postnatal week in the rat is a sensitive period in cerebellar development to dysregulation by inflammation. This sensitive period is characterized by increased production of prostaglandins, in particular PGE2. This sensitive period coincides with a time of increased risk for perinatal H/I (e.g. birth in human infants). The source of the stunting of the Purkinje neuron dendritic tree following inflammation is unknown. Microglia are the brains innate immune cells and serve a variety of functions in both health and disease. We have observed tightly regulated and temporally controlled phagocytic activity of microglia in the developing cerebellum and we hypothesize this plays an important role in normal cerebellar development. We provide evidence that H/I at PN10 increases still further the peak in phagocytosis normally seen at PN17. One of the key signals regulating microglia phagocytic activity is the membrane lipid phosphatidylserine, which is externalized to the outer leaflet and promotes phagocytosis. Hypoxia has been known to stimulate phagocytosis by stressing cells sufficiently to externalize phosphotidylserine. The role of metabolism or lipid rafts in the externalization of this lipid has not been considered, nor have either of these variables been characterized in microglia in a surveying versus activated state. Hypoxic-Ischemic brain injury often occurs following an inflammatory insult, resulting in further injury than would otherwise occur. Whether this is true in the developing cerebellum has not been carefully explored nor have sex differences in hypoxic-ischemic brain or inflammatory injury been considered. We propose three Specific Aims focused on 1) morphometery of Purkinje neurons, granule cells and the deep cerebellar nuclei following H/I with and without inflammation, 2) the role of microglia in neuronal damage induced by H/I with and without inflammation and 3) the impact of tetracycline based antibiotic, Minocycline, as proof of principle and the glutamate transporter modifying antibiotic Ceftriaxone as a potential therapeutic. We will also explore the dietary supplement, choline and conduct behavioral and histological analyses to assess injury and recovery. Data generated by these experiments will provide novel insights into the impact of H/I on the cerebellum and the degree to which it contributes to the impaired cognitive and motor function seen in infants suffering hypoxic-ischemic encephalopathy.

项目概要： 神经元发育的敏感期因大脑区域、对破坏性物质的敏感性和脆弱性而异。我们 发现大鼠出生后第二周是小脑发育的敏感期 炎症引起的失调。这个敏感期的特点是前列腺素的产生增加， 特别是PGE2。这个敏感期恰逢围产期 H/I 风险增加的时期（例如人类出生） 婴儿）。炎症后浦肯野神经元树突树发育迟缓的根源尚不清楚。小胶质细胞 是大脑的先天免疫细胞，在健康和疾病中发挥多种功能。我们严密观察 发育中小脑中小胶质细胞的调节和暂时控制的吞噬活性，我们假设 这在正常小脑发育中起着重要作用。我们提供证据表明 PN10 时的 H/I 仍在增加 此外，吞噬作用的峰值通常出现在 PN17。调节小胶质细胞吞噬活性的关键信号之一是 膜脂磷脂酰丝氨酸，其外化到外叶并促进吞噬作用。缺氧 已知它可以通过对细胞施加足够的压力来刺激吞噬作用，从而使磷脂酰丝氨酸外化。的作用 尚未考虑该脂质外化中的代谢或脂筏，也没有考虑这些变量中的任何一个 已对小胶质细胞处于调查状态与激活状态进行了表征。 缺氧缺血性脑损伤通常发生在炎症损伤后，导致比普通损伤更严重的损伤 否则会发生。这对于正在发育的小脑是否属实还没有被仔细探索过，也没有发生过性行为 考虑了缺氧缺血性脑或炎症损伤的差异。我们提出三个具体目标 1) 浦肯野神经元、颗粒细胞和小脑深部核团在 H/I 有或没有的情况下的形态测量 炎症，2) 小胶质细胞在 H/I 引起的神经元损伤中的作用，有或没有炎症，3) 基于四环素的抗生素米诺环素的影响作为原理证明和谷氨酸转运蛋白修饰 抗生素头孢曲松作为一种潜在的治疗方法。我们还将探讨膳食补充剂、胆碱和行为 行为和组织学分析以评估损伤和恢复。这些实验产生的数据将提供 关于 H/I 对小脑的影响及其对认知受损程度的新见解 患有缺氧缺血性脑病的婴儿中观察到的运动功能和运动功能。