Genes in Human Brain Ischemia
人脑缺血的基因
基本信息
- 批准号:8048271
- 负责人:
- 金额:$ 20万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-15 至 2012-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAlzheimer&aposs DiseaseApolipoprotein EBiochemical MarkersBiological MarkersBloodBrainBrain InjuriesBrain IschemiaCalpainCandidate Disease GeneCause of DeathCerebral IschemiaCerebrumClinicalCombination Drug TherapyDevelopmentEnrollmentEnvironmentExerciseFunctional disorderGenesGenetic PolymorphismGenomicsGenotypeGoalsHeart ArrestHeat shock proteinsHumanIschemiaIschemic Brain InjuryKnowledgeLeadModalityN-terminalNeurofilament-HNeurologicOperating RoomsOperative Surgical ProceduresOutcomePathway interactionsPatientsPerfusionPeroxidasesPharmaceutical PreparationsPharmacotherapyPhysiologyProteinsRelative (related person)ReportingResearchResistanceRiskRoleSeminalStereotypingStrokeSyndromeTestingTherapeuticTherapeutic StudiesTherapy Clinical TrialsUnited StatesVariantVenousWeightWorkalpha Spectrinaortic archbasedesigndisabilitygene discoverygene therapyhigh riskimprovednerve injuryneuroprotectionneurotoxicitynovelprogramspublic health relevance
项目摘要
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.
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,已被证明对已在人体中测试的大多数疗法具有抗性。这项研究的总体目标是发现最合适的基因,用于随后的单基因和多基因治疗和药物治疗。研究患者在主动脉弓手术期间接受深低温停循环(DHCA)和不完全逆行脑灌注(RCP)的常规缺血性挑战;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的多态性将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),均具有影响脑缺血易感性的先前证据,将评估其对DHCA和RCP后急性神经损伤的六个定量指标的贡献(S-1002、NSE、高磷酸化神经丝H、低磷酸化神经丝H、去磷酸化神经丝H和钙蛋白酶衍生的α-血影蛋白N-末端片段)。 H2。与缺血后脑损伤病理生理学中大多数已知主要机制相关的基因多态性将影响结果。在相关基因发现的练习中,将检查91种基于病理生理学的基因型,以确定其对DHCA和RCP后急性神经损伤的定量指标(与H1中相同的6种生物标志物)的可能贡献。对于每个特定目标,急性神经损伤的定量指标将包括来自脑流入和RCP流出血液以及手术后静脉血的脑损伤的已知生化标志物。将入组200例DHCA患者。 从这种背景中获得的关于基因组脆弱性的信息不仅会导致手术期间管理此类患者的方法的改变,而且可能更重要的是,将产生在与全脑缺血和中风相关的许多非手术背景中有用的信息。由于中风是美国第三大死亡原因和主要残疾原因,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。
公共卫生关系:手术室环境提供了一个独特的机会,研究基因组变异缺血的脆弱性,或多或少的定型不完全脑缺血发生相当可预测的。从这种情况下获得的关于基因组脆弱性的信息不仅会导致手术期间管理此类患者的方法的变化,而且可能更重要的是,将产生在与全脑缺血和中风相关的许多非手术环境中使用的信息。由于中风是美国第三大死亡原因和主要残疾原因,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治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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W ANDREW KOFKE其他文献
W ANDREW KOFKE的其他文献
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