In vivo injury paradigms

体内损伤范例

• 批准号: 6224459
• 负责人: GARY K STEINBERG
• 金额: $ 18.53万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6224459
• 关键词: Adenoviridae; Alphaherpesvirinae; BCL2 gene /protein; antioxidants; cell death; cerebral ischemia /hypoxia; disease /disorder model; electron microscopy; gene induction /repression; immunocytochemistry; laboratory rat; neuropathology; neuroprotectants; protooncogene; stress proteins; superoxide dismutase; transfection; transfection /expression vector; transient ischemic attack

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.

脑卒中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。基因诱导已经观察到缺血后，但许多确切的作用还不清楚。已知一些基因产物对细胞有害，而另一些基因产物被认为是神经保护性的。该项目的目标是更精确地定义三类可能发挥神经保护作用的基因的作用。它们是：原癌基因bcl-2，抗氧化基因（sod-1和gspx）和应激蛋白hsp 70。在项目2中，我们将利用遗传学正常的动物并研究3种不同的缺血体内模型（2种局灶性和1种全脑缺血模型）。我们将通过使用缺陷型单纯疱疹病毒和腺病毒载体进行基因转移来改变基因表达。我们将研究基因过度表达可能改善神经元存活的限制和条件。我们假设，由于一些，但不是其他种类的侮辱将减弱与基因产物的过度表达，这些观察将提供深入了解细胞死亡的病理生理。我们将研究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对永久性和短暂性局灶性脑缺血具有保护作用。我们还将通过研究其他基因产物（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研究神经保护或缺乏神经保护的机制。我们还将研究基因的过度表达是否会改变超氧化物和细胞凋亡的产生。这些新的方法有望增加对脑缺血所涉及的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的发展。