BCL-2 FAMILY GENES AND TBI

BCL-2 家族基因和 TBI

• 批准号: 6445547
• 负责人: STEVEN H GRAHAM
• 金额: $ 6.52万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/6445547
• 关键词: BCL2 gene /protein; apoptosis; brain injury; disease /disorder model; gene expression; genetically modified animals; laboratory mouse; oxidative stress; pathologic process; trauma

Bcl-2 family genes have a key role in controlling programmed cell death in neurons. We have found evidence that bcl-2 family genes are dysregulated and PCD occurs in both animal models and TBI in humans. The hypothesis of this proposal is that altered expression of bcl-2 family gene occurs after brain trauma and contributes to programmed cell death, oxidative stress, neuronal death, and adverse behavioral outcome. Specific aims are as follows: 1. Characterize alterations in expression of the bcl-2 family genes (including bcl-2, bcl-x, Bax) that occur after CCI in mice. 2. Test whether bcl-2 expression inhibits PCD, oxidative stress and improves histological and behavioral outcome after CCI by use of a transgenic mouse that over-expresses bcl-2. 3. Test whether Bax expression is necessary to trigger PCD after CCI, and whether Bax expression mediates oxidative stress, adverse histological and behavioral outcome by use of Bax-disrupted transgenic mice subjected to CCI. 4. Test whether over-expression of bcl-x-1 by replication deficient herpes simplex viral vectors can protect hippocampal neurons against CCI. 5. Determine if similar alterations in bcl-2 family expression occur in human TBI by examining expression of bcl-2 and Bax in human tissue removed during decompressive craniotomies and CSF from ventriculostomies. Furthermore, determine if there is evidence of apoptosis in CSF (nucleosomes). Correlate these findings with long term outcome as determined by the Glasgow outcome score (GOS) and other measures. The proposed experiments address the key issues regarding the alteration of bcl-2 family genes in traumatic brain injury: Do bcl-2 family genes regulate cell death after trauma or is their altered expression an epiphenomena in cells already destined to live or die, and are these changes relevant to human head trauma? If these experiments support the hypothesis that bcl-2 family genes regulate cell death after trauma, alteration of expression of these genes or mimicking or inhibiting their effects could provide new strategies for treatment of traumatic brain injury.

Bcl-2 家族基因在控制神经元程序性细胞死亡中发挥着关键作用。我们发现证据表明 bcl-2 家族基因失调，动物模型中发生 PCD，人类发生 TBI。该提议的假设是，脑外伤后 bcl-2 家族基因的表达发生改变，并导致程序性细胞死亡、氧化应激、神经元死亡和不良行为结果。具体目标如下： 1. 表征小鼠 CCI 后 bcl-2 家族基因（包括 bcl-2、bcl-x、Bax）表达的变化。 2. 使用过度表达 bcl-2 的转基因小鼠测试 bcl-2 表达是否抑制 PCD、氧化应激并改善 CCI 后的组织学和行为结果。 3.通过使用遭受CCI的Bax破坏的转基因小鼠来测试Bax表达是否是CCI后触发PCD所必需的，以及Bax表达是否介导氧化应激、不良组织学和行为结果。 4. 测试复制缺陷型单纯疱疹病毒载体过度表达 bcl-x-1 是否可以保护海马神经元免受 CCI 侵害。 5. 通过检查开颅减压术中取出的人体组织和脑室造口术中取出的脑脊液中 bcl-2 和 Bax 的表达，确定 bcl-2 家族表达是否发生在人类 TBI 中。此外，确定脑脊液（核小体）中是否存在细胞凋亡的证据。将这些发现与格拉斯哥结果评分 (GOS) 和其他指标确定的长期结果相关联。拟议的实验解决了关于创伤性脑损伤中 bcl-2 家族基因改变的关键问题：bcl-2 家族基因是否调节创伤后细胞死亡，或者它们的表达改变是否是已经注定要生存或死亡的细胞中的附带现象？这些变化与人类头部外伤有关吗？如果这些实验支持bcl-2家族基因调节创伤后细胞死亡的假设，那么改变这些基因的表达或模仿或抑制它们的作用可以为治疗创伤性脑损伤提供新的策略。