In vivo injury paradigms

体内损伤范例

基本信息

批准号：
6480799
负责人：
GARY K STEINBERG
金额：
$ 15.58万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-03-01 至 2002-02-28
项目状态：
已结题

项目摘要

Recent progress in the area of stroke research suggests that a number of molecular mechanisms are intimately involved in the evolution of ischemic brain injury. Gene induction has been observed following ischemia, but the exact roles of many are not yet well known. Some gene products are known to be detrimental to the cell while others are felt to be neuroprotective. The goals of this project are to define more precisely the roles of three classes of genes which may play neuroprotective roles. They are: the proto oncogene, bcl-2, antioxidant genes (sod-1 and gspx) and the stress protein, hsp70. In Project 2, we will utilize genetically normal animals and study 3 different in vivo models of ischemia (2 focal and one global models of cerebral ischemia). We will alter gene expression via gene transfer using defective herpes simplex and adenoviral vectors. We will study the limits and conditions under which gene over-expression may improve neuron survival. We hypothesize that injury due to some, but not other kinds of insults will be attenuated with gene product over-expression, and that these observations will offer insight into the pathophysiology of cell death. We will examine whether gene transfer after the onset of injury is neuroprotective, and whether over-expression of Bcl-2 and antioxidant genes are protective against permanent as well as transient focal cerebral ischemia. We will also examine mechanisms underlying neuroprotection, or lack of neuroprotection, by examining the participation of other gene products such as the stress proteins, caspases and Bcl-2 family proteins in response to gene over-expression and cerebral injury. We will also study whether gene over-expression alters generation of superoxide and apoptosis. These novel approaches will hopefully add insight into the complex molecular processes involved in cerebral ischemia and may lead to the development of treatments for stroke and other degenerative disorders.

中风研究领域的最新进展表明，许多分子机制与缺血性脑损伤的演变密切相关。缺血后已观察到基因诱导，但许多基因的确切作用尚不清楚。已知一些基因产物对细胞有害，而另一些则被认为具有神经保护作用。该项目的目标是更准确地定义可能发挥神经保护作用的三类基因的作用。它们是：原癌基因 bcl-2、抗氧化基因（sod-1 和 gspx）和应激蛋白 hsp70。在项目 2 中，我们将利用基因正常的动物来研究 3 种不同的体内缺血模型（2 种局部脑缺血模型和一种整体脑缺血模型）。我们将使用有缺陷的单纯疱疹病毒和腺病毒载体通过基因转移来改变基因表达。我们将研究基因过度表达可以提高神经元存活率的限制和条件。我们假设，某些而非其他类型的损伤造成的损伤会随着基因产物的过度表达而减弱，并且这些观察结果将为细胞死亡的病理生理学提供深入的了解。我们将检查损伤发生后的基因转移是否具有神经保护作用，以及 Bcl-2 和抗氧化基因的过度表达是否可以预防永久性和短暂性局灶性脑缺血。我们还将通过检查其他基因产物（例如应激蛋白、半胱天冬酶和 Bcl-2 家族蛋白）对基因过度表达和脑损伤的反应来检查神经保护或缺乏神经保护的机制。我们还将研究基因过度表达是否会改变超氧化物的产生和细胞凋亡。这些新方法有望增加对脑缺血相关复杂分子过程的了解，并可能导致中风和其他退行性疾病治疗方法的开发。