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的程序性细胞死亡中具有关键作用。我们发现证据表明Bcl-2家族基因失调，PCD在人类的动物模型和TBI中都发生。该提议的假设是，Bcl-2家族基因的表达改变发生在脑创伤后发生，并导致编程的细胞死亡，氧化应激，神经元死亡和不良行为结果。具体目的如下：1。表征在小鼠中CCI后发生的Bcl-2家族基因（包括Bcl-2，Bcl-X，BAX）的表达变化。 2。测试Bcl-2表达是否抑制PCD，氧化应激并通过使用过表达Bcl-2的转基因小鼠后CCI后改善组织学和行为结果。 3。测试Bax表达是否需要在CCI后触发PCD，以及Bax表达是否通过使用受CCI约束的Bax脱离的转基因小鼠介导氧化应激，不良组织学和行为结果。 4。通过复制缺乏单纯疱疹病毒向量测试Bcl-x-1是否可以保护海马神经元免受CCI的影响。 5。确定在人类TBI中，通过检查室中颅骨术中去除的人体组织中的Bcl-2和Bax的表达，在人类TBI中是否发生了类似的改变。此外，确定CSF（核小体）中凋亡的迹象是否有证据。将这些发现与长期结局相关联，该结果由格拉斯哥结果评分（GOS）和其他措施确定。拟议的实验解决了脑损伤中Bcl-2家族基因改变的关键问题：DO Bcl-2家族基因调节创伤后的细胞死亡，或者它们的表达改变是已经注定要生存或死亡的细胞中的Epiphenomena这些变化与人头创伤有关？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，则这些基因表达的改变或模仿或抑制其作用可能会为治疗创伤性脑损伤的治疗提供新的策略。