MOLECULAR BIOLOGY OF APOPTOSIS IN IRRADIATED NEURONS

细胞凋亡是细胞死亡的重要机制 在发育和受伤后。 在神经元中，众所周知， 生长因子的去除可以在体内， 和体外培养。 最近，我们的实验室已经表明，电离辐射（IR） 诱导有丝分裂后背根神经节（DRG）神经元凋亡， 体外 IR诱导细胞凋亡的能力显著下降， 在培养的前3周，21天大的DRG神经元 不经历辐射诱导的凋亡。 以前在非神经元 细胞已经表明，细胞凋亡的发生是由于IR产生的DNA， 损伤需要p53的诱导。 p53表达增加导致 许多下游基因的激活，包括p21，GADD 45， mdm-2，但最近的证据表明，它是p53之间的相互作用， 和bc 1 -2基因家族成员（包括bc 1 -2、bc 1-x（L）和bax） 这决定了是否会发生细胞凋亡。 本提案中所述的实验将专门针对 p53、bax、bc 1 -2和bc 1 - 3的各自作用和相互作用 x（L）对有丝分裂后DRG神经元凋亡程序的调控 暴露在电离辐射下 我们还将研究这些 蛋白质在DRG敏感性的时间变化中起作用 神经元的IR。通过识别的相互作用的关键决定 无论这些神经元在暴露于IR后存活还是死亡，我们都可能是 能够设计合理的策略来保护神经元免受其他神经元的伤害， 可能致命的侮辱

Apoptosis now is recognized to be an important mechanism of cell death during development and after injury. In neurons, it is well known that growth factor withdrawal can produce apoptotic cell death, both in vivo, and in vitro. Recently, our lab has shown that ionizing radiation (IR) induces apoptosis in post-mitotic dorsal root ganglion (DRG) neurons in vitro. The ability of IR to induce apoptosis dramatically declined over the first 3 weeks in culture to the point where 21 day old DRG neurons did not undergo radiation-induced apoptosis. Previous work in non-neuronal cells has shown that apoptosis occurring as a result of IR-produced DNA damage requires induction of p53. Increased expression of p53 results in activation of a number of downstream genes, including p21, GADD45, and mdm-2, but recent evidence suggests that it is the interaction between p53 and members of the bc1-2 gene family (including bc1-2, bc1-x(L), and bax) that determines whether apoptotic cell death will occur. The experiments described in this proposal will specifically address the individual roles of, and interactions between, p53, bax, bc1-2, and bc1- x(L) in regulating the apoptosis program in post-mitotic DRG neurons exposed to ionizing radiation. We will also examine the roles that these proteins play in producing the temporal change in sensitivity of DRG neurons to IR. By identifying the interactions critical for determining whether these neurons survive or die following exposure to IR, we may be able to design rational strategies for protecting neurons from other potentially lethal insults.