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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

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.

项目总体概要新生儿缺氧缺血（H/I）仍然是一个主要的健康问题，治疗方法有限。生活对婴儿和护理人员的长期影响要求我们增加对起源的了解，出生前后脑损伤的后果和预防。临床证据越来越多地指出小脑作为一个受到新生儿 H/I 和这种损害影响深远但更广泛的区域当与其共享相互联系的区域遭受额外损害时，就会产生回响。然而在新生儿 H/I 的临床前模型中，小脑在很大程度上被忽略了。该提案在术语中对 H/I 进行了建模人类婴儿时期，是小脑高度敏感的时期。狭隘敏感期间发生的侮辱时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影响。通常，新生儿 H/I 会因早期且可能未被发现的神经炎症而加剧。因此我们建议对新生儿 H/I 后发育中的小脑（有或没有）进行深入的首次分析之前有炎症。我们通过三个具体目标来解决这个问题。 SA1：开发 H/I 期动物模型有或没有既往炎症，对小脑损伤的临床证据具有构建有效性新生儿。 SA2：整合与相关的神经解剖学、代谢、信号转导和行为终点该动物模型中的小脑损伤。 SA3：测试抑制药物的神经保护作用神经炎症，恢复新陈代谢和/或防止失调的信号转导，从而产生为不久的将来的翻译奠定临床前基础。这些目标将通过四个独立的通过提供动物、组织学和行为测试来保证项目和协同作用行为核心（核心 B）。每个项目均由一名专家 PI 领导。项目 I (McCarthy) - 小胶质细胞作为大脑的先天免疫系统及其在正常小脑发育中的作用以及对损伤的影响，项目 II (McKenna) - 新陈代谢及其对损伤的反应和作用，以及项目 III (Bearer) - 脂筏重要的信号传导元件被 H/I 和炎症破坏。项目 IV（Waddell），R03 试点项目，探索了眨眼条件反射的新颖用途，这是一种众所周知的小脑控制学习范式，评估新生儿 H/I 的认知影响。小胶质细胞既能响应炎症，又能产生炎症，如果没有被捕，就变成了逃跑且持久的病态反应。新陈代谢和能量利用是 H/I 后损伤的重要决定因素，高能量区域的风险更大，包括小脑。 MALDI-MSI 成像的使用将提供与脂质、神经递质、氧化物质相关的详细高分辨率压力和新陈代谢。脂筏是神经发育的关键组成部分，但它们在很大程度上被在 H/I 的背景下尚未探索。所有实验都包括相同数量的男性和女性。一起这些项目将突出可以在当前临床实践中轻松实施的新治疗目标。