BIOLOGY AND PHARMACOLOGY OF THE GDNF HOMOLOG NEURTURIN

在杰弗里·米尔布兰特博士的实验室的合作下，我们最近 分离和克隆了一种新的神经营养因子--神经突触蛋白 与胶质细胞源性神经营养因子(GDNF)同源。Neurturin是 基于其阻止交感神经元死亡的能力而提纯 剥夺神经生长因子(NGF)。有人提出的实验将会 研究其生理功能和药理作用。 神经突触素。我们将检测神经管蛋白在Northern中的表达。 和RT-PCR分析以及原位杂交，并通过 免疫组织化学，在发育期和成年大鼠。特别关注 将支付给成年的中枢神经系统。对损伤的反应的表达 将对神经系统进行检查。我们将检查神经突起的能力 对多种神经元和神经细胞发挥促进存活或营养作用 培养中的造血细胞类型。此外，我们还将研究 ~(125)I-Neurturin和内源性Neurturin在大鼠体内的逆行转运 成人三叉神经节和中枢神经系统。我们将确定神经突触蛋白的生理作用。 通过两种互补的方法。首先，我们将分析神经突触 米尔布兰特实验室培育出的“基因敲除”小鼠。第二，我们将研究 神经肽中和抗体对胎儿、新生儿和 成年大鼠，以及受到损伤的大鼠。我们将研究一下 神经节苷脂外源性给药的药理作用 新生大鼠。我们将检查神经节苷脂是否有能力改善 免疫、机械和化学侮辱对交感神经的影响 活体神经元和其他神经元类型有待鉴定。我们会 对比和比较营养促进和生存促进作用的模式 NGF、白血病抑制因子(LW)联合应用对神经细胞生长的影响 交感神经元。我们将同样地比较潜在的信号 促进生存和生长的信号转导机制 这些因素的促进作用。 这些研究将确定生理作用和药理作用。 神经突触素的作用。这样的结果可能表明了这一点的潜力 因子作为神经退行性疾病、中风或 神经元损伤。

In collaboration with the lab of Dr.Jeffrey Milbrandt, we have recently isolated and cloned a novel neurotrophic factor, neurturin, that bears homology to glial cell-derived neurotrophic factor (GDNF). Neurturin was purified based on its ability to block sympathetic neuron death after nerve growth factor (NGF) deprivation. Experiments are proposed that will examine the physiological functions and pharmacological actions of neurturin. We shall examine the expression of neurturin mRNA by Northern and RT-PCR analysis and by in situ hybridization, and neurturin protein by immunohistochemistry, in developing and adult rats. Particular attention will be paid to the adult CNS. Expression in response to injury to the nervous system will be examined. We shall examine the ability of neurturin exert survival-promoting or trophic effects on a variety of neuronal and hematopoietic cell types in culture. In addition we shall examine the retrograde transport of 125I- neurturin and endogenous neurturin in the adult PNS and CNS. We shall determine the physiological roles of neurturin by two complementary approaches. First, we shall analyze neurturin "knockout" mice generated in the Milbrandt lab. Secondly, we will examine the effects of neurturin neutralizing antibodies on fetal, neonatal, and adult rats, and in rats subjected to injury. We shall examine the pharmacological effects of neurturin when administered exogenously to neonatal rats. We shall examine the ability of neurturin to ameliorate the effects of immunological, mechanical, and chemical insults to sympathetic neurons in vivo and other neuronal types to be identified. We shall contrast and compare the pattern of trophic and survival promoting effects of neurturin with that of NGF and leukemia inhibitory factor (LW) on sympathetic neurons. We shall similarly compare potential signal transduction mechanisms mediating the survival promoting and growth promoting effects of these factors. These studies will define the physiological role and pharmacological actions of neurturin. Such results may indicate the potential of this factor as a therapeutic agent in neurodegenerative disease, stroke, or neuronal injury.