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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.

整体项目总结新生儿缺氧缺血(H/I)仍然是一个主要的健康问题，治疗方法有限。《生活》对婴儿和照顾者的长期影响要求我们增加关于起源的知识，出生前后脑损伤的后果和预防。越来越多的临床证据表明作为一个受新生儿缺氧缺乏症和这种损害影响更深但更广泛的区域的小脑随着其他损害随之而来，与其有互惠联系的地区也会产生反响。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。人类婴儿，小脑高度敏感的时期。在狭隘的敏感时期发生的侮辱经期可以通过破坏永远不能重置的动态发展过程而产生持久的影响。新生儿缺氧缺乏症通常会因早期的神经炎症而加重，而且可能未被察觉。因此，我们建议对新生儿缺氧缺血后发育中的小脑进行首例深入分析先前的炎症。我们有三个具体的目标来解决这个问题。SA1：建立H/I期动物模型有和没有先前的炎症对小脑损伤的临床证据具有构造性有效性新生儿。SA2：整合与以下相关的神经解剖、代谢、信号转导和行为终端在这个动物模型中，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/或防止信号转导失调，从而创造为近期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、组织学和动物和动物的行为测试来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家PI领导。项目I(麦卡锡)--小胶质细胞作为大脑的天然免疫系统及其在正常小脑发育中的作用和对损伤的影响二(麦肯纳)--新陈代谢及其对损害的反应和作用，以及项目三(承担者)--脂筏必要的信号元件被H/I和炎症破坏。项目IV(Waddell)，R03试点项目，探索眨眼条件作用的新用途，这是一种著名的小脑控制学习范式，以评估新生儿H/I对认知的影响小胶质细胞既对炎症做出反应，也会产生炎症，如果不被抓，成为一种逃跑和持久的病理反应。新陈代谢和能量使用是一种脑缺血后损伤的重要决定因素，高能区风险较大，包括小脑。使用MALDI-MSI成像将提供与血脂、神经递质、氧化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在H/I的背景下未被探索。所有的实验包括相同数量的雄性和雌性。把这些放在一起项目将突出新的治疗目标，这些目标可以很容易地在当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.