TRH AND NEURONAL APOPTOSIS

促甲状腺激素释放激素(TRH)在下丘脑外的作用 中枢神经系统(CNS)的区域尚不清楚，但已经 被认为是这些细胞中的神经递质或神经调节器 地点。人们已经认识到，各种神经肽， 包括P物质(SP)在内，可能具有神经营养因子的作用。 最近，我们实验室报告了(摘要)转染人 用腺病毒载体培养胎鼠下丘脑 反义TRH基因可导致神经细胞死亡。这一发现 增加了TRH不仅作为一种 下丘脑释放因子也是一种神经营养因子 中枢神经系统。一些神经营养因子(或保护神经元的因子 完整性)已在中枢神经系统中被描述，包括脑源性 已报道共定位的神经营养因子(BDNF) 和TRH一起。因此，我们推测TRH和BDNF可能会合作 在中枢神经系统中作为神经营养因子(或作为细胞凋亡的抑制因子)。 也有证据表明BDNF与BCL-2家族相互作用。 原癌基因在调控细胞凋亡过程中的作用一个可能的 TRH“敲除”可诱导神经元死亡的机制 TRH可能与BDNF协同作用影响细胞凋亡， 作为一种细胞凋亡过程的抑制因子或作为bcl2 激活剂，刺激bcl2，防止细胞死亡。 这一提议旨在检验TRH是一种 神经元维持所需的神经营养因子 CNS并通过BDNF-2家族与BDNF合作 原癌基因在神经元凋亡过程中的作用这些研究 可能与退行性神经病的发病机制有关 阿尔茨海默氏症或帕金森氏症等疾病 就像正常增长一样。

The role of Thyrotropin Releasing Hormone (TRH) in extra hypothalamic areas of the central nervous system(CNS) is unclear but has been thought to act as a neurotransmitter or neuromodulater in these locations. It has been recognized that various neural peptides, including substance P (SP), may function as neurotropic factors. Recently, our laboratory reported (in abstract) that transfection of fetal rat hypothalamic cultures with an adenovirus containing an antisense rat TRH cDNA led to neuronal cell death. This finding raises the possibility that TRH may function not only as an hypothalamic releasing factor but also as a neurotrophic factor in CNS. A number of neurotrophins (or factors that preserve neuronal integrity) have been described in the CNS including brain-derived neurotrophic factor (BDNF) which has been reported to be colocalized with TRH. Accordingly we speculate that TRH and BDNF may cooperate as neurotrophic factors (or as inhibitor of apoptosis) in the CNS. There is also evidence that BDNF interacts with the bcl-2 family of protooncogenes in regulating the apoptotic process. A possible mechanism through which a TRH "knockout" could induce neuronal death is that TRH may cooperate with BDNF to influence the apoptosis, either as an inhibitor of the apoptosis process or as a bcl-2 activator to stimulate bcl-2 to prevent cell death. This proposal is designed to test the hypothesis that TRH is a neurotrophic factor necessary for the maintenance of neurons in the CNS and that it cooperates with BDNF through the Bcl-2 family of protooncogenes in the process of neuronal apoptosis. These studies may have relevance to the pathogenesis of degenerative neurologic disorders such as Alzheimer's disease or Parkinson's disease as well as normal gaining.