Genes in Human Brain Ischemia

描述（由申请人提供）：脑缺血后的脑损伤仍然是一个临床挑战，已被证明对大多数在人类中测试过的治疗具有耐药性。该研究的总体目标是发现最合适的基因，用于后续开发单一和多侧面基因和药物治疗。研究主动脉弓手术中伴有深度低温循环停止（DHCA）和不完全逆行脑灌注（RCP）的患者的典型缺血挑战；我们的具体目标是检验以下假设：H1。与神经保护、神经毒性和阿尔茨海默病相关的候选基因多态性可以预测缺血后脑损伤的程度。三种基于病理生理学的基因型，载脂蛋白E (ApoE)，热休克蛋白（HSP）和髓过氧化物酶（MPO），都有先前的证据表明对脑缺血易感性有影响，将评估DHCA合并RCP后急性神经损伤的六个定量指标（S-1002， NSE，高磷-神经丝H，低磷-神经丝H，去磷-神经丝H和calpain衍生的α -谱蛋白n端片段）的贡献。H2。与脑缺血后脑损伤病理生理机制相关的基因多态性将影响预后。在相关基因发现的练习中，91个基于病理生理学的基因型将被检查可能对DHCA合并RCP后急性神经损伤的定量指标（与H1中相同的6个生物标志物）的贡献。对于每个特定目的，急性神经损伤的定量指标将包括手术后脑流入血和RCP流出血以及静脉血中已知的脑损伤生化标志物。200名DHCA患者将被纳入研究。从这种基因组易感性中获得的信息不仅会改变手术期间对这类患者的治疗方法，而且，也许更重要的是，将产生的信息将用于许多与全脑缺血和中风相关的非手术环境。由于中风是美国第三大死亡原因和致残原因，因此这项研究的影响可能非常重大，可能导致中风或其他脑缺血综合征的基因或新药或基因治疗。

DESCRIPTION (provided by applicant): Brain damage after cerebral ischemia continues to be a clinical challenge that has proven to be resistant to most therapies that have been tested in humans. The overall objective of the proposed research is to discover the most appropriate genes for subsequent development of single and multifacet gene and drug therapies. Studying patients sustaining a stereotypical ischemic challenge during aortic arch surgery with deep hypothermic circulatory arrest (DHCA) and incomplete retrograde cerebral perfusion (RCP); our specific aims are to test the following hypotheses: H1. Polymorphisms in candidate genes associated with neuroprotection, neurotoxicity, and Alzheimer's disease will predict extent of brain injury after ischemia. Three pathophysiologically based genotypes, apolipoprotein E (ApoE), heat shock protein (HSP), and myeloperoxidase(MPO), all with prior evidence of an effect in vulnerability to brain ischemia, will be evaluated for contribution to six quantitative indicators of acute neural injury after DHCA with RCP (S-1002, NSE, hyperphospho-neurofilament H, hypophospho-neurofilament H, dephospho- neurofilament H, and a calpain-derived N-terminal fragment of alpha-spectrin). H2. Polymorphisms in genes associated with most known major mechanisms in the pathophysiology of brain damage after ischemia will affect outcome. In an exercise in relevant gene discovery, 91 pathophysiologically based genotypes will be examined for possible contribution to a quantitative indicator (the same six biomarkers as in H1) of acute neural injury after DHCA with RCP. For each specific aim quantitative indicators of acute neural injury will include the known biochemical markers of brain damage from brain inflow and RCP effluent blood and venous blood after surgery. Two hundred DHCA patients will be enrolled. Information derived from this setting about genomic vulnerability will not only lead to changes in approach to management of such patients during surgery, but also, and perhaps more importantly, will generate information that will be of use in many non- operative settings associated with global brain ischemia and stroke. As stroke is the third leading cause of death and leading cause of disability in the United States, the impact of this research may be very significant, possibly leading to gene or new drug or gene therapy of stroke or other brain ischemia syndromes. PUBLIC HEALTH RELEVANCE: The operating room environment provides a unique opportunity for study of genomic variation in ischemic vulnerability, as more or less stereotypical incomplete cerebral ischemia occurs fairly predictably. Such information derived from this setting about genomic vulnerability will not only lead to changes in approach to management of such patients during surgery, but also, and perhaps more importantly, will generate information that will be of use in many non-operative settings associated with global brain ischemia and stroke. As stroke is the third leading cause of death and leading cause of disability in the United States, the impact of this research may be very significant, possibly leading to gene or new drug therapy of stroke or other brain ischemia syndromes.