NEUROTROPHIC REGULATION OF NEURONAL SIGNALING

描述：（申请人的摘要）已经取得了巨大的进展， 在其受体中识别新的神经营养因子， 表征它们在神经元存活和分化中的作用。 毫不奇怪，神经营养相互作用的异常已经被发现。 与包括癫痫在内的多种神经系统疾病有关， 帕金森氏症。 然而，目前对 神经营养调节的基本神经元功能的基础， 这些过程和紊乱，如神经元信号传导， 相当有限。 这项研究计划的目标是了解神经营养 因子调节神经元兴奋性和突触传递。 实验方法将是研究如何表达和 单个离子通道和神经递质受体的功能 是由特定的神经营养因子调节的。 具体目标 1）为了验证trk受体决定细胞增殖的假设， 神经营养素作用的特异性。 这一假设将是 在离子通道调节的背景下进行测试， 不同神经营养因子的神经递质受体表达， trk受体; 2）确定是否使用神经营养因子， 完全不相关的信号转导机制有共同的 监管行动。 这一特定目标的假设是， 不相关的神经营养因子会对 所有神经元共有的兴奋特性，但对 特殊神经元特有的兴奋特性。 这 将针对不相关的因素NGF和睫状体检验假设 神经营养因子;和3）确定神经营养因子是否 调节短期内的兴奋性。 神经营养因子的激活 因子受体如trk受体启动多个 神经营养因子结合数分钟内的信号级联。 做 这些信号事件，其中许多已知会影响 在其他情况下的兴奋性，导致离子的短期调制 渠道功能？ 拟议的研究将使用电生理，分子 生物学和光学成像技术来研究 离子通道和神经递质受体的功能 在三个实验环境中的物种：神经元细胞系，细胞 用特异性神经营养因子受体转染， 海马神经元的培养。 结果从这些 实验将有助于理解神经营养 因子调节重要的神经元功能，例如兴奋性， 突触传递，以及神经营养缺乏如何 相互作用可导致神经元功能障碍和神经系统疾病。 紊乱

DESCRIPTION: (Applicant's Abstract) Tremendous progress has been made in identifying new neurotrophic factors in their receptors, and in characterizing their roles in neuronal survival and differentiation. Not surprisingly, abnormalities in neurotrophic interactions have been implicated in several neurological disorders including epilepsy and Parkinson's disease. However, current understanding of the neurotrophic regulation of the basic neuronal functions that underlie these processes and disorders, such as neuronal signaling, remains quite limited. The goal of this research proposal is to understand how neurotrophic factors regulate neuronal excitability and synaptic transmission. The experimental approach will be to study how the expression and function of individual ion channels and neurotransmitter receptors are regulated by defined neurotrophic factors. The specific aims are: 1) To test the hypothesis that trk receptors determine the specificity of action of the neurotrophins. This hypothesis will be tested in the context of the regulation of ion channel and neurotransmitter receptor expression by different neurotrophins and trk receptors; 2) To determine if neurotrophic factors that use completely unrelated signal transduction mechanisms have common regulatory actions. The hypothesis of this specific aim is that unrelated neurotrophic factors will have overlapping effects on excitable properties common to all neurons, but distinct effects on excitable properties unique to particular neuronal types. This hypothesis will be tested for the unrelated factors NGF and ciliary neurotrophic factor; and 3) To determine if neurotrophic factors modulate excitability in the short-term. Activation of neurotrophic factor receptors such as the trk receptors initiates multiple signaling cascades within minutes of neurotrophic factor binding. Do these signaling events, many of which are known to affect excitability in other contexts, cause short term modulation of ion channel function? The proposed studies will use electrophysiological, molecular biological, and optical imaging techniques to study the expression and function of individual ion channel and neurotransmitter receptor species in three experimental settings: neuronal cell lines, cells transfected with specific neurotrophic factor receptors, and primary cultured neurons from hippocampus. The results from these experiments will contribute to the understanding of how neurotrophic factors regulate important neuronal functions such as excitability and synaptic transmission, and how deficiencies in neurotrophic interactions can lead to neuronal dysfunction and neurological disorders.