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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：
9979910
负责人：
CYNTHIA FRANCES BEARER
金额：
$ 126.68万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979910
关键词：
Achievement Acute Brain Injuries Animal Behavior Animal Model Animal Testing 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 Event Exhibits Exposure to Female Foundations Future Gene Expression Goals Health Hippocampus (Brain)Histologic Histology Human Image Impairment Infant Inflammation Injury Innate Immune System Knowledge Laboratory Rat Learning Life Lipids Literature Live Birth Membrane Microdomains Metabolic Metabolism Microglia Modeling Molecular Morbidity - disease rate Motor Natural regeneration Neurologic Neurotransmitters Newborn Infant Nodal Oxidative Stress Pathologic Perinatal Hypoxia Pilot Projects Pre-Clinical Model Prefrontal Cortex Prevention Preventive Intervention Rattus Recovery Resolution Rice Risk Rodent Role Running Series Sex Differences Signal Transduction Source Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Standardization Testing Therapeutic Therapeutic Intervention Time Transference Translations Trees Variant Work behavior test clinical practice clinically relevant conditioning emotional behavior experimental study insight interdisciplinary approach male mortality natural hypothermia neonatal hypoxic-ischemic brain injury neonate neurodevelopment neuroinflammation new therapeutic target novel perinatal period postnatal pre-clinical premature prevent programs response response to injury sex social synergism 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.

总体项目摘要新生儿缺氧缺血（H/I）仍然是一个主要的健康问题，治疗方法有限。生命对婴儿和照顾者的长期影响要求我们增加关于起源的知识，在出生时的后果和预防脑损伤。越来越多的临床证据表明小脑作为一个区域，受到新生儿H/I的深刻但更广泛的影响，作为额外的损害，对与其共享相互联系的区域进行反射。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视。本提案模拟H/I在术语人类婴儿，小脑高度敏感的时期。发生在狭窄敏感期间的侮辱月经周期会使动态的发展过程脱轨，从而产生持久的影响，而这种过程永远无法重置。新生儿H/I通常与早期的、可能未被发现的神经炎症复合。因此，我们建议对新生儿H/I后小脑发育进行深入的首次分析，先前的炎症我们以三个具体目标来解决这个问题。SA 1：建立晚期H/I动物模型有和没有先前的炎症，对于小脑损伤的临床证据具有结构效度，新生儿SA 2：整合与以下相关的神经解剖学、代谢、信号转导和行为终点：小脑损伤的动物模型。SA 3：测试抑制神经细胞增殖的药物的神经保护作用神经炎症，恢复代谢和/或防止失调的信号转导，从而产生一种新的神经炎症。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的通过提供动物、动物组织学和行为测试确保项目和协同作用，行为核心（核心B）。每个项目都由一名专业PI领导。项目I（麦卡锡）-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和对损伤的影响， II（McKenna）-代谢及其对损害的反应和作用，以及项目III（Bearer）-脂筏作为 H/I和炎症破坏的重要信号传导元件。项目IV（Waddell），一个R 03试点项目，探讨了眨眼条件反射的新用途，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。小胶质细胞既响应又产生炎症，如果而不是被逮捕，成为一个逃跑和持久的病理反应。代谢和能量利用是一个 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、氧化还原酶、神经递质和神经递质相关的详细的高分辨率。压力和新陈代谢。脂筏是神经发育的重要组成部分，但它们在很大程度上在H/I的背景下未被探索。所有实验包括相同数量的雄性和雌性。综合这些项目将突出新的治疗目标，可以很容易地在目前的临床实践中实施。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Choline Improves Neonatal Hypoxia-Ischemia Induced Changes in Male but Not Female Rats.

DOI：
10.3390/ijms232213983
发表时间：
2022-11-12
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

Neonatal hypoxia ischemia redistributes L1 cell adhesion molecule into rat cerebellar lipid rafts.

DOI：
10.1038/s41390-022-01974-4
发表时间：
2022-11
期刊：
PEDIATRIC RESEARCH
影响因子：
3.6
作者：
Waddell, Jaylyn;Rickman, Nicholas C.;He, Min;Tang, Ningfeng;Bearer, Cynthia F.
通讯作者：
Bearer, Cynthia F.

Prognostic MRS in neonatal encephalopathy: closer to generalizability.