Apoptosis Induced by Traumatic Brain Injury

脑外伤诱导的细胞凋亡

• 批准号: 6871362
• 负责人: ALAN Ira FADEN
• 金额: $ 32.82万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871362
• 关键词: apoptosis; biological signal transduction; brain injury; cysteine endopeptidases; enzyme activity; laboratory rat; nerve injury; neuroprotectants; phosphorylation; protease inhibitor; protein kinase; protooncogene; tissue /cell culture; trauma; tumor suppressor proteins

DESCRIPTION (Adapted from applicant's abstract): Traumatic brain injury (TBI) or traumatic neuronal injury (TNT) in vitro causes neuronal apoptosis, in part, through activation of caspase-3-like proteases. inhibition of caspase-3 in vitro reduces posttraumatic cell death and provides additive neuroprotection to that produced by agents that inhibit necrotic cell death. Caspase-3 activation is modulated by upstream caspases, including caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway). Our preliminary data suggests that the caspase-9 pathway appears to be more important in neurotrauma. Akt (protein kinase B) is a well-established anti-apoptotic factor, which may act, in part, by modulating caspase activation. Akt itself can also be modulated by several factors, including the novel tumor suppression protein PTEN. Recent experiments in our laboratory have suggested a role for PTEN in neuronal apoptosis. We propose to examine the role of Akt in neuronal apoptosis after TB! and TNT, and elucidate the critical upstream and downstream signal transduction pathways involved. Specific hypotheses include: 1) caspase-9, but not caspase-8, represents an important upstream modulatory mechanism for caspase-3 mediated apoptosis after trauma; 2) Akt plays an important modulatory role in apoptosis following TBI or TN! in vitro; 3) Anti-apoptotic actions of Akt include inhibition of caspase-3 activation by phosphorylating the pro-apoptotic factor BAD, as well as through other non-caspase mechanisms; 4) The recently identified tumor suppressor factor PTEN is activated after trauma or trophic withdrawal and contributes to neuronal apoptosis, in part, by downregulating Akt activity; and 5) Development of PTEN antagonists may provide a novel neuroprotective treatment strategy for CNS injury. We propose the following specific aims: 1) To examine the relative contributions of the intrinsic (caspase-9) and extrinsic (caspase-8) pathways in modulating caspase-3-induced apoptosis in TB! and TNT, using complementary in vivo and in vitro model systems; 2) To establish an anti-apoptotic role for Akt in TBI and TNT and examine proposed mechanisms, including phosphorylation of BAD. 3) To demonstrate a pro-apoptotic role for PTEN in TBI and TNI, and show that this action results substantially from its ability to downregulate Akt, resulting in activation of caspase-9 and caspase-3; and 4) To show that PTEN antagonists, newly developed by us in collaboration, are neuroprotective following injury in vivo and in vitro.

描述（改编自申请人摘要）：创伤性脑损伤（TBI） 或创伤性神经元损伤（TNT）在体外引起神经元凋亡，部分地， 通过激活半胱天冬酶-3样蛋白酶。caspase-3抑制 体外减少创伤后细胞死亡并提供额外的神经保护 与抑制坏死细胞死亡的药剂产生的那些相比。Caspase-3 激活由上游半胱天冬酶调节，包括半胱天冬酶-9（内在的 途径）和胱天蛋白酶-8（外源性途径）。我们的初步数据显示， 半胱天冬酶-9途径在神经创伤中似乎更重要。 Akt（蛋白激酶B）是一种公认的抗凋亡因子，其可以 部分通过调节半胱天冬酶的活化而起作用。Akt本身也可以是 受几种因素的调节，包括新的肿瘤抑制蛋白 PTEN。我们实验室最近的实验表明，PTEN在 神经元凋亡 我们建议检查Akt在TB后神经元凋亡中的作用！TNT， 并阐明关键的上游和下游信号转导途径 涉案具体的假说包括：1）caspase-9，而不是caspase-8， 代表了caspase-3介导的重要上游调节机制， Akt在创伤后细胞凋亡中起重要调节作用 在TBI或TN之后！3）Akt的抗凋亡作用包括 通过磷酸化促凋亡因子抑制半胱天冬酶-3活化 BAD，以及通过其他非半胱天冬酶机制; 4）最近 已鉴定的肿瘤抑制因子PTEN在创伤或营养不良后被激活。 戒断，并有助于神经元凋亡，部分通过下调， Akt活性;和5）PTEN拮抗剂的开发可以提供新的治疗方法。 CNS损伤的神经保护治疗策略。 我们提出了以下具体目标：1）检查相对 内源性（caspase-9）和外源性（caspase-8）途径的作用 在结核病中调节caspase-3诱导的细胞凋亡！和TNT，使用互补的 在体内和体外模型系统; 2）建立抗凋亡作用， Akt在TBI和TNT中的作用，并检查提出的机制，包括磷酸化 的坏。3)证明PTEN在TBI和TNI中的促凋亡作用， 表明这种作用实质上是由于其下调 Akt，导致半胱天冬酶-9和半胱天冬酶-3的活化;和4）为了显示， 我们合作开发的新的PTEN拮抗剂具有神经保护作用， 在体内和体外损伤后。

项目成果

Presence of DNA Fragmentation and Lack of Neuroprotective Effect in DFF45 Knockout Mice Subjected to Traumatic Brain Injury

遭受创伤性脑损伤的 DFF45 基因敲除小鼠中存在 DNA 碎片且缺乏神经保护作用

• 发表时间: 2001
• 期刊: Molecular Medicine
• 影响因子: 5.7
• 作者: A. Yakovlev;X. Di;V. Movsesyan;Paul G. M. Mullins;Geping Wang;Hamid A. Boulares;Jianhua Zhang;Ming Xu;A. Faden
• 通讯作者: A. Faden

Over-expression of HSP70 attenuates caspase-dependent and caspase-independent pathways and inhibits neuronal apoptosis.

HSP70的过表达可减弱caspase依赖性和caspase独立的途径，并抑制神经元凋亡。

• DOI: 10.1111/j.1471-4159.2012.07927.x
• 发表时间: 2012-11
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Sabirzhanov B;Stoica BA;Hanscom M;Piao CS;Faden AI
• 通讯作者: Faden AI