Neurogenesis Following Hypoxic Ischemic Neonatal Brain Injury

新生儿缺氧缺血性脑损伤后的神经发生

• 批准号: 8067623
• 负责人: MARGARET M. MCCARTHY
• 金额: $ 19.3万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067623
• 关键词: Adult; Amino Acids; Animals; Behavioral; Birth; Brain; Bromodeoxyuridine; Bumetanide; Calcium; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chloride Ion; Chlorides; Cognitive; Data; Development; Estradiol; Estrogen Therapy; Female; Gender; Goals; Gonadal Steroid Hormones; Hippocampus (Brain); Hour; Hyperoxia; Hypoxia; In Vitro; Individual; Injury; Instruction; Intellectual functioning disability; Ischemia; Laboratories; Lead; Measures; Mediating; Mediator of activation protein; Metabolic; Microglia; Modeling; Muscimol; Neonatal; Neonatal Brain Injury; Neurons; Neuropil; Neurotransmitters; Outcome; Oxidative Stress; Periderm; Phase; Prevention; Principal Investigator; Proliferating; Recovery; Recovery of Function; Research; Resuscitation; Role; Series; Sex Characteristics; Side; Source; Stem cells; Survival Rate; Testing; The Sun; Therapeutic; Therapeutic Intervention; Up-Regulation; clinical practice; dentate gyrus; functional outcomes; gamma-Aminobutyric Acid; improved; in vivo; injured; insight; male; neonatal hypoxic-ischemic brain injury; neonate; nerve stem cell; neurogenesis; novel therapeutics; prevent; regenerative; research study; response; subventricular zone

instnjctions): Emphasis on how cells die and protecting against further death after neonatal hypoxic/ischemia (H/l) has provided much needed therapeutic interventions. Recent emphasis has focused on recovery from injury and turned to the stimulatory effects of H/l on a pool of neural stem cells located in the subventricular zone (SVZ), and progenitor cells in the germinal zone of the dentate gyrus. We have recentiy identified an additional source of neuronal progenitor cells located within the neuropil of Ammon's horn in the developing hippocampus (Zhang et al., 2007). In uninjured animals, the rate of proliferation is almost twice as high in male neonates as females and the gonadal steroid, estradiol, is a potent stimulator of cell genesis in this region as well as the dentat gyrus. We will use the Vannuci model of H/l to explore whether proliferating cells in the dentate gyrus or within Ammon's horn are influenced by estradiol and whether sex, steroids and/or normoxic versus hyperoxic conditions post-injury impact on the proliferation response. Pilot data indicates that hyperoxia following H/l quickly results in a massive upregulation of cell proliferation on the injured side ofthe brain and that many of these cells are microglia. We will test a series of related HYPOTHESES; 1) H/l injury induces cell genesis in the developing hippocampus in two phases, an eariy microglia proliferation (within hours) followed by a later neurogenesis that peaks 7 days later, 2) estradiol reduces microglial proliferation but enhances neurogenesis. 3) H/l enhances excitatory GABA responses and 4) estradiol enhances it still further, which is the mechanism mediating increased neurogenesis and 5) increased neurogenesis after H/l promotes functional recovery. These hypotheses will be tested by experiments under four Specific Aims which include in vivo an in vitro cellular analyses and extensive characterization of functional outcome. The translational significance of these studies is the potential for new therapeutic treatments to enhance both the proliferation and survival of new neurons following H/l in neonates. The mechanistic significance is identification of the source of sex differences in response to neonatal H/l and the cellular processes by which estradiol can lead to improved outcomes following damage. RELEVANCE (See instructions): Currently available therapeutic options following neonatal H/l focus on prevention of further damage. The experiments proposed here will open the gateway to regenerative therapeutics that can restore lost neurons and provide recovery of function and will do so with consideration of the imporant variable of gender of the injured individual.

指令）： 强调新生儿缺氧/缺血 (H/l) 后细胞如何死亡并防止进一步死亡 提供了急需的治疗干预措施。最近的重点集中在伤病恢复和 转向 H/l 对位于脑室下区的神经干细胞库的刺激作用 （SVZ）和齿状回生发区的祖细胞。我们最近发现了一个 位于发育中的阿蒙角神经毡内的神经元祖细胞的额外来源 海马体（Zhang et al., 2007）。在未受伤的动物中，增殖率几乎是未受伤动物的两倍 男性新生儿与女性新生儿一样，而性腺类固醇雌二醇是细胞发生的有效刺激剂 区域以及齿状回。我们将使用H/l的Vannuci模型来探讨增殖细胞是否 齿状回或阿蒙角内的细胞受到雌二醇的影响，以及性别、类固醇和/或 常氧与高氧条件对损伤后增殖反应的影响。试点数据表明 H/l 后的高氧很快会导致受伤侧细胞增殖大量上调 大脑的细胞，其中许多细胞是小胶质细胞。我们将测试一系列相关的假设； 1) 高/升 损伤会诱导发育中的海马细胞发生两个阶段，即早期小胶质细胞增殖 （数小时内）随后出现神经发生，并在 7 天后达到峰值，2) 雌二醇减少小胶质细胞 增殖但增强神经发生。 3) H/l 增强兴奋性 GABA 反应和 4) 雌二醇 进一步增强它，这是介导神经发生增加的机制，5）增加 H/l后的神经发生促进功能恢复。这些假设将通过实验进行检验 四个具体目标，包括体内和体外细胞分析以及广泛的表征 功能结果。这些研究的转化意义在于新疗法的潜力 增强新生儿 H/1 后新神经元的增殖和存活的治疗。这 机制意义在于确定新生儿 H/l 反应中性别差异的来源以及 雌二醇可以改善损伤后的结果的细胞过程。 相关性（参见说明）： 目前新生儿 H/l 后可用的治疗方案侧重于预防进一步的损伤。这 这里提出的实验将为再生疗法打开大门，可以恢复丢失的神经元 并提供功能恢复，这样做时将考虑到性别这一重要变量 受伤的个人。