BIOLOGY AND PHARMACOLOGY OF THE GDNF HOMOLOG NEURTURIN

与杰弗里·米尔布兰特博士的实验室合作，我们最近 分离并克隆了一种新的神经营养因子neurturin， 与胶质细胞源性神经营养因子（GDNF）同源。Neurturin是 基于其阻断交感神经元死亡的能力， 神经生长因子（NGF）剥夺。提出的实验将 研究的生理功能和药理作用 neurturin。我们将通过北方免疫荧光法检测neurturin mRNA的表达。 和RT-PCR分析和原位杂交，和neurturin蛋白， 免疫组化，在发展和成年大鼠。特别注意 将支付给成人CNS。表达对损伤的反应 将检查神经系统。我们将检验Neurturin 对多种神经元发挥存活促进或营养作用， 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在脑组织中的逆行转运 成人PNS和CNS。我们将确定neurturin的生理作用 两种互补的方法。首先，我们将分析neurturin 在米尔布兰特实验室中产生的“敲除”小鼠。其次，我们将研究 neurturin中和抗体对胎儿、新生儿和 成年大鼠和遭受损伤的大鼠。我们将研究 neurturin的药理作用时，外源性给药， 新生大鼠我们将检查neurturin改善 免疫、机械和化学损伤对交感神经系统的影响 体内神经元和其他待鉴定的神经元类型。我们将 对比和比较营养和存活促进效应的模式 neurturin与NGF和白血病抑制因子（LW）对 交感神经元我们将类似地比较潜在信号 介导存活促进和生长的转导机制 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 Neurturin的作用。这样的结果可能表明， 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.