Mechanisms of Hypothermic Neuroprotection in Neonates

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，亚低温是治疗新生儿缺氧缺血性脑病的唯一方法，但效果不完全。45%的接受治疗的婴儿在HI后仍然死亡或持续严重的神经发育障碍。设计安全、有效、机械化的新型辅助疗法是这一研究领域的重中之重。总之，有必要开发基于机械的、可靠的生物标记物来跟踪新的治疗方法并衡量其有效性。我们发现程序性坏死是新生儿缺氧缺血性脑病的一种损伤机制，这为寻找新的治疗方法提供了机会。程序性坏死在新生儿HI中是可行的，这在临床上是令人信服的。程序性坏死不同于经典的坏死，它是可调节的、可治疗的，并且在体外很好地被理解。低温如何以及是否能抑制程序性坏死尚不清楚，对新生儿缺氧缺血性脑病辅助治疗的成功发展非常重要。低温和程序性坏死抑制剂的体内神经靶点也是我们知识中的一个空白。低温对神经元的影响是众所周知的。人们对低温对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。胶质细胞、少突胶质细胞和星形胶质细胞是新生儿缺氧缺血性脑病的主要原因。尤其是星形胶质细胞，可能在低温和程序性坏死抑制剂启动和保护HI的过程中发挥关键作用。由于星形胶质细胞释放胶质纤维酸蛋白(GFAP)可能参与了缺氧缺血性脑损伤的启动和反应，因此可能是我们寻找的可靠的、区域性的、基于机制的生物标志物。在这项提案中，我们将使用已建立的新生儿缺氧和低体温模型来解决每一个研究重点和领域的知识差距。我们将检验这一假设，即低温通过阻断程序性坏死来为新生儿缺氧缺血性脑病提供神经保护。随后，使用这些实验的数据，我们将测试低温、抗程序性坏死和抗细胞凋亡治疗作为实验生物标志物治疗新生儿HI和GFAP的组合。通过这样做，我们将在新生儿脑损伤研究中开辟新的途径。这些实验解决了新生儿脑损伤中的关键、及时和高度相关的问题。 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；寻找新的治疗方法，与我们目前对新生儿缺氧缺血性脑损伤的治疗相结合。此外，我们将把一种有前景的临床生物标记物应用于实验模型，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毁灭性损伤的治疗的理解。

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.