Effects of Perinatal Hypoxia-Ischemia on the Developing Cerebellum With and Without Prior Inflammation

围产期缺氧缺血对有或没有炎症的小脑发育的影响

基本信息

批准号：
9151504
负责人：
CYNTHIA FRANCES BEARER
金额：
$ 127.85万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-17 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9151504
关键词：
Achievement Acute Brain Injuries Animal Behavior Animal Model Animals Area Attention Behavior Behavioral Birth Blinking Brain Brain Hypoxia-Ischemia Brain Injuries Brain region Caregivers Cell Respiration Cerebellum Clinical Cognitive Cognitive deficits Common Core Development Developmental Process Diffuse Elements Energy Metabolism Event Exhibits Female Foundations Future Gene Expression Goals Head Health Hippocampus (Brain)Histology Human Image Immune system Impairment Infant Inflammation Injury Knowledge Laboratory Rat Learning Life Lipids Literature Live Birth Membrane Microdomains Metabolic Metabolism Microglia Modeling Molecular Morbidity - disease rate Motor Natural regeneration Neonatal Neurologic Neurotransmitters Newborn Infant Nodal Oxidative Stress Perinatal Perinatal Hypoxia Pilot Projects Pre-Clinical Model Prefrontal Cortex Prevention Preventive Intervention Rattus Recovery Resolution Rice Risk Rodent Role Running Series Sex Characteristics Shapes Signal Transduction Source Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Testing Therapeutic Therapeutic Intervention Time Transference Translations Trees Variant Work behavior test clinical practice clinically relevant conditioning emotional behavior insight interdisciplinary approach male mortality natural hypothermia neonatal hypoxic-ischemic brain injury neonate neurodevelopment neuroinflammation new therapeutic target novel postnatal pre-clinical premature prevent programs research study response response to injury sex social translational study

Achievement Acute Brain Injuries Animal Behavior Animal Model Animals Area Attention Behavior Behavioral Birth Blinking Brain Brain Hypoxia-Ischemia Brain Injuries Brain region Caregivers Cell Respiration Cerebellum Clinical Cognitive Cognitive deficits Common Core Development Developmental Process Diffuse Elements Energy Metabolism Event Exhibits Female Foundations Future Gene Expression Goals Head Health Hippocampus (Brain)Histology Human Image Immune system Impairment Infant Inflammation Injury Knowledge Laboratory Rat Learning Life Lipids Literature Live Birth Membrane Microdomains Metabolic Metabolism Microglia Modeling Molecular Morbidity - disease rate Motor Natural regeneration Neonatal Neurologic Neurotransmitters Newborn Infant Nodal Oxidative Stress Perinatal Perinatal Hypoxia Pilot Projects Pre-Clinical Model Prefrontal Cortex Prevention Preventive Intervention Rattus Recovery Resolution Rice Risk Rodent Role Running Series Sex Characteristics Shapes Signal Transduction Source Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Testing Therapeutic Therapeutic Intervention Time Transference Translations Trees Variant Work behavior test clinical practice clinically relevant conditioning emotional behavior insight interdisciplinary approach male mortality natural hypothermia neonatal hypoxic-ischemic brain injury neonate neurodevelopment neuroinflammation new therapeutic target novel postnatal pre-clinical premature prevent programs research study response response to injury sex social translational study

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项目摘要

Overall Project Summary Neonatal hypoxia-ischemia (H/I) remains a major health issue with limited therapeutic approaches. The life long consequences to both infant and caregivers demands we increase our knowledge regarding the origins, consequences and prevention of brain damage around the time of birth. Clinical evidence increasingly points to the cerebellum as a region that is profoundly but more diffusely impacted by neonatal H/I and this damage reverberates as additional damage ensues to the regions with which it shares reciprocal connections. Yet the cerebellum has been largely ignored in preclinical models of neonatal H/I. This proposal models H/I in the term human infant, a time of heightened sensitivity for the cerebellum. Insults that occur during narrow sensitive periods can have enduring effects by derailing dynamic developmental processes that can never be reset. Often neonatal H/I is compounded by earlier, and perhaps undetected, neuroinflammation. Thus we propose to conduct an in-depth first-of-its-kind analysis of the developing cerebellum after neonatal H/I with and without prior inflammation. We attack the question with three Specific Aims. SA1: Develop an animal model of term H/I with and without prior inflammation that has construct validity for clinical evidence of cerebellar damage in newborns. SA2: Integrate neuroanatomical, metabolic, signal transduction and behavioral endpoints relevant to cerebellar damage in this animal model. SA3: Test the neuroprotective effects of agents that inhibit neuroinflammation, restore metabolism and/or prevent dysregulated signal transduction and thereby create a preclinical foundation for translation in the immediate future. These aims will be achieved via four independent projects and synergy assured by provision of animals, histology and behavioral testing from the Animal and Behavioral Core (Core B). Each project is headed by an expert PI. Project I (McCarthy) - microglia as the brain's innate immune system and their role in normal cerebellar development and impact on damage, Project II (McKenna) - metabolism and its response to and role in damage, and Project III (Bearer) - lipid rafts as essential signaling elements disrupted by H/I and inflammation. Project IV (Waddell), an R03 pilot project, explores the novel use of eye blink conditioning, a well known cerebellar controlled learning paradigm, to assess the cognitive impact of neonatal H/I. Microglia both respond to and produce inflammation which can, if not arrested, become a run away and enduring pathological response. Metabolism and energy use is an important determinant of damage following H/I, with high energy areas at greater risk, including the cerebellum. Use of MALDI-MSI imaging will provide detailed high resolution relevant to lipids, neurotransmitters, oxidative stress and metabolism. Lipid rafts are critical components of neural development yet they have been largely unexplored in the context of H/I. All experiments include equal numbers of males and females. Together these projects will highlight new therapeutic targets that can be easily implemented in current clinical practice.

总体项目摘要新生儿缺氧 - 缺血（H/I）仍然是有限的治疗方法的主要健康问题。生活对婴儿和看护人的长期影响要求我们增加有关起源的知识，出生时间左右的后果和预防脑损伤。临床证据越来越多点对小脑作为一个深刻但受到新生儿H/I影响的区域，这种损害随着与与之共享相互连接的区域的额外损害发生回响。但是在新生儿H/I的临床前模型中，小脑在很大程度上被忽略了。该建议在该期间模型H/I 人类婴儿，对小脑的敏感性提高。狭窄敏感的侮辱周期可以通过破坏永远无法重置的动态发展过程来产生持久的效果。通常，新生儿H/I更早期，也许未被发现了神经炎症。因此，我们建议在新生儿H/I之后，对发育中的小脑进行了深入的首次分析，有或没有先前的炎症。我们以三个特定目标来攻击问题。 SA1：开发术语h/i的动物模型有和没有先前的炎症，具有构建有效性的小脑损害的临床证据的有效性新生儿。 SA2：整合神经解剖学，代谢，信号转导和行为终点小脑损害该动物模型。 SA3：测试抑制剂的神经保护作用神经炎症，恢复新陈代谢和/或防止信号转导失调，从而创建一个在不久的将来翻译的临床前基础。这些目标将通过四个独立通过提供动物的动物，组织学和行为测试的项目和协同作用行为核心（核心B）。每个项目都由专家PI领导。项目I（McCarthy） - 小胶质细胞为大脑的先天免疫系统及其在正常小脑发育中的作用和对损害的影响，项目 II（McKenna） - 代谢及其对损害中的反应和作用，项目III（承载） - 脂质筏作为 H/I和炎症破坏的基本信号元件。 R03试点项目IV项目（Waddell），探索眼睛眨眼条件的新颖使用，这是一种众所周知的小脑控制的学习范式，评估新生儿H/I的认知影响。小胶质细胞既应对并产生炎症，如果没有被捕，成为逃跑并持久的病理反应。代谢和能源使用是 H/I后损害的重要决定因素，高能量区域的风险更大，包括小脑。使用MALDI-MSI成像将提供与脂质，神经递质，氧化有关的详细高分辨率压力和代谢。脂质筏是神经发育的关键组成部分，但它们在很大程度上是在h/i的上下文中未开发。所有实验包括相等数量的男性和女性。在一起项目将重点介绍可以在当前临床实践中轻松实施的新的治疗靶标。