Mechanisms of Hypothermic Neuroprotection in Neonates

新生儿低温神经保护机制

• 批准号: 8370698
• 负责人: FRANCES J NORTHINGTON
• 金额: $ 33.31万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-17 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370698
• 关键词: Acids; Address; Adjuvant Therapy; Affect; Apoptosis; Area; Astrocytes; Biochemistry; Biological Markers; Birth; Brain Injuries; Caring; Cell Death; Chemicals; Child; Clinical; Country; Data; Development; Discipline of obstetrics; Encephalopathies; Experimental Models; Failure; Glial Fibrillary Acidic Protein; Hybrid Cells; Hypoxia; Immunohistochemistry; Immunoprecipitation; In Vitro; Incidence; Infant; Injury; Ischemic-Hypoxic Encephalopathy; Knowledge; Life; Measures; Modeling; Necrosis; Neonatal; Neonatal Brain Injury; Neurodevelopmental Disability; Neuroglia; Neurons; Oligodendroglia; Outcome; Outcome Measure; Pathway interactions; Play; Pre-Clinical Model; Protein Kinase; Proteins; RIPK3 gene; Research; Research Priority; Resources; Role; Serum; Severities; Signal Transduction; Testing; base; crosslink; design; disability; forging; human RIPK1 protein; improved; in vivo; inhibitor/antagonist; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonate; neurobehavioral; neuroimaging; neuropathology; neuroprotection; novel; programs; relating to nervous system; research study; response; response to injury; small hairpin RNA; tool

DESCRIPTION (provided by applicant): Neonatal hypoxic-ischemic (HI) brain injury results in devastating, life-long disability for the affected children. At present, hypothermia is the only treatment for neonatal HI and it is incompletely effective. 45% of treated infants still die or sustain severe neurodevelopmental disability following HI. Designing safe, effective, mechanistically novel adjuvant therapies is the highest priority in this field of research. In concert, there is a need to develop mechanistically-based, reliable biomarkers to track novel therapies and measure their efficacy. Our identification of programmed necrosis as a mechanism of injury in neonatal HI provides an opportunity to identify novel therapies. That programmed necrosis may be operative in neonatal HI is clinically compelling. Programmed necrosis, unlike classical necrosis, is regulated, treatable, and is well understood in vitro. How and whether hypothermia acts to inhibit programmed necrosis is unknown and very important to the successful development of adjuvant therapies for neonatal HI. The in vivo neural target of hypothermia and programmed necrosis inhibitors is also a gap in our knowledge. Effects of hypothermia on neurons are best known. Little is known about the effects of hypothermia on glia and nothing is known about the effects of programmed necrosis inhibitors. Glia, oligodendroglia and astrocytes, clearly contribute to the overall "encephalopathy" resulting from neonatal HI. Astrocytes, in particular, may play a pivotal role in initiation of and protection from HI by both hypothermia and programmed necrosis inhibitors. Because of their possible involvement in the initiation and response to HI injury and treatment, astrocytic release of glial fibrillary acid proein (GFAP) may be the reliable, regionally specific, mechanistically-based biomarker that we seek for neonatal HI brain injury. In this proposal, we will use an established model of neonatal HI and hypothermia address each of these research priorities and areas of knowledge gap. We will test the hypothesis that hypothermia provides neuroprotection following neonatal HI by interrupting programmed necrosis. Subsequently, using data from these experiments we will test combinations of hypothermia, anti-programmed necrosis and anti-apoptosis treatments for treatment of neonatal HI and GFAP as an experimental biomarker. In doing so we will forge new pathways in neonatal brain injury research These experiments address critical, timely, and highly relevant issues in neonatal brain injury. PUBLIC HEALTH RELEVANCE: These studies address one of the highest priorities in neonatal brain injury; finding novel therapies to combine with our current treatment for neonatal hypoxic ischemic brain injury. Additionally, we will be applying a promising clinical biomarker to an experimental model, to test its ability to predict severity of injury and response to treatment. Results from these studies have the potential to fundamentally alter our understanding of how hypoxic ischemic injury causes brain damage and how to significantly improve treatment for this devastating injury.

描述（由申请人提供）：新生儿缺氧缺血（HI）脑损伤会导致受影响儿童毁灭性的终身残疾。目前，低温治疗是新生儿HI的唯一治疗方法，且效果不完全。 45% 接受治疗的婴儿在 HI 后仍然死亡或患有严重的神经发育障碍。设计安全、有效、机制新颖的辅助疗法是该研究领域的首要任务。同时，需要开发基于机制的可靠生物标志物来跟踪新疗法并测量其疗效。我们将程序性坏死确定为新生儿 HI 损伤机制，这为确定新疗法提供了机会。程序性坏死可能在新生儿 HI 中起作用，这一点在临床上令人信服。与经典坏死不同，程序性坏死是可调节的、可治疗的，并且在体外已被充分了解。低温如何以及是否能够抑制程序性坏死尚不清楚，但对于成功开发新生儿 HI 辅助疗法非常重要。低温和程序性坏死抑制剂的体内神经靶标也是我们知识的空白。低温对神经元的影响是众所周知的。人们对低温对神经胶质细胞的影响知之甚少，对程序性坏死抑制剂的影响也一无所知。神经胶质细胞、少突胶质细胞和星形胶质细胞显然与新生儿 HI 引起的整体“脑病”有关。特别是星形胶质细胞，可能在低温和程序性坏死抑制剂引起的 HI 引发和保护中发挥关键作用。由于星形胶质细胞可能参与 HI 损伤和治疗的启动和反应，因此星形胶质细胞释放的胶质原纤维酸性蛋白 (GFAP) 可能是我们寻找新生儿 HI 脑损伤的可靠、区域特异性、基于机制的生物标志物。在本提案中，我们将使用已建立的新生儿 HI 和低温模型来解决每个研究重点和知识差距领域。我们将检验这样的假设：低温通过中断程序性坏死来提供新生儿 HI 后的神经保护。随后，利用这些实验的数据，我们将测试低温、抗程序性坏死和抗细胞凋亡治疗的组合，作为实验生物标志物治疗新生儿 HI 和 GFAP。在此过程中，我们将为新生儿脑损伤研究开辟新途径。这些实验解决了新生儿脑损伤中关键、及时且高度相关的问题。 公共卫生相关性：这些研究解决了新生儿脑损伤的最高优先事项之一；寻找新的疗法与我们目前治疗新生儿缺氧缺血性脑损伤的方法相结合。此外，我们将把一种有前途的临床生物标志物应用于实验模型，以测试其预测损伤严重程度和治疗反应的能力。 这些研究的结果有可能从根本上改变我们对缺氧缺血性损伤如何导致脑损伤以及如何显着改善这种破坏性损伤的治疗的理解。