BIOLOGY AND PHARMACOLOGY OF THE GDNF HOMOLOG NEURTURIN

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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.