MOLECULAR ANALYSIS OF NERVE GROWTH FACTOR ACTION

描述：神经细胞的存活依赖于许多营养因子， 影响，其中神经生长因子（NGF）是最广泛的 学习和理解。 这项拨款提案的长期目标是 了解神经细胞存活的分子机制。 NGF家族 包括脑源性神经营养因子和神经营养素_3和NT_4/5。 这些蛋白质中的每一种与两种不同的跨膜受体相互作用， Trk酪氨酸激酶亚家族成员和p75神经营养因子 受体，TNF受体家族的成员。 这些行为 受体决定发育过程中神经元细胞的数量。 共表达 p75与TRK家族成员的结合可能发挥许多关键功能， 包括当营养因子被 仅以限制浓度存在;酪氨酸激酶的调节 活性;和不同的神经营养因子之间的更大的歧视。 此外，利用鞘脂周转的新型信号传导途径是 被神经营养因子和细胞因子用作另一种潜在的信号转导 介导凋亡的机制。 神经营养因子作用的选择性是 可能依赖于受体系统，其中trk的共表达 p75家族成员导致了独特的下游生物学效应， 应答 该建议将集中在受体结合和信号传导 对NGF的要求。 这项研究对以下机制有影响： 神经元细胞群的细胞存活、分化和细胞死亡， 这将最终影响我们对许多神经退行性疾病的理解， 疾病，如运动神经元和阿尔茨海默氏痴呆症。

DESCRIPTION: Neuronal cell survival is dependent upon many trophic influences, of which nerve growth factor (NGF) has been the most extensively studied and understood. The long term goal of this grant proposal is to understand the molecular mechanism of nerve cell survival. The NGF family includes brain derived neurotrophic factor and neurotrophins_3 and NT_4/5. Each of these proteins interacts with two different transmembrane receptors, members of the trk tyrosine kinase subfamily and the p75 neurotrophin receptor, a member of the TNF family of receptors. The actions of these receptors determine neuronal cell numbers during development. Co_expression of p75 with trk family members may play a number of crucial functions, including increasing the affinity of ligand binding when trophic factors are present only in limiting concentrations; regulation of tyrosine kinase activity; and greater discrimination between different neurotrophin factors. Additionally, novel signaling pathways utilizing sphingolipid turnover are used by neurotrophins and cytokines as another potential signal transduction mechanism to mediate apoptosis. Selectivity of neurotrophin action is likely to depend upon adual receptor system in which coexpression of trk family members with p75 result in distinctive downstream biological responses. This proposal will focus upon the receptor binding and signaling requirements for NGF. The investigation has implications for mechanisms of cell survival, differentiation and cell death of neuronal cell populations, which will ultimately bear upon our understanding of many neurodegenerative diseases, such as motor neuron and Alzheimer's dementia.