Mechanisms of Hypothermic Neuroprotection in Neonates

描述（由申请人提供）：新生儿缺氧缺血性（HI）脑损伤导致受影响儿童的毁灭性终身残疾。目前，新生儿HI的治疗方法只有低温治疗，但效果不完全。45%的治疗婴儿在HI后仍然死亡或患有严重的神经发育障碍。设计安全、有效、机械新颖的辅助疗法是该研究领域的最高优先级。因此，需要开发基于机械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损伤的一种机制，这为确定新的治疗方法提供了机会。程序性坏死可能在新生儿HI中起作用，这在临床上是令人信服的。与经典坏死不同，程序性坏死是可调控的、可治疗的，并且在体外被充分理解。低温如何以及是否抑制程序性坏死是未知的，对于新生儿HI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的空白。低温对神经元的影响是众所周知的。关于低温对胶质细胞的影响知之甚少，关于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明显导致新生儿HI引起的总体“脑病”。星形胶质细胞，特别是，可能发挥关键作用，在启动和保护HI的低温和程序性坏死抑制剂。由于它们可能参与HI损伤的启动和反应以及治疗，星形胶质细胞释放胶质细胞酸性蛋白（GFAP）可能是我们寻找的新生儿HI脑损伤的可靠的、区域特异性的、基于机械的生物标志物。在本提案中，我们将使用新生儿HI和体温过低的既定模型来解决这些研究重点和知识差距领域中的每一个。我们将检验低温通过中断程序性坏死提供新生儿HI后神经保护的假设。随后，使用来自这些实验的数据，我们将测试低温、抗程序性坏死和抗细胞凋亡治疗的组合用于治疗新生儿HI和GFAP作为实验生物标志物。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关键、及时和高度相关的问题。

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.