How Ephexin Signaling Promotes Neuronal Stability

Ephexin 信号如何促进神经元稳定性

• 批准号: 7509540
• 负责人: CARL ANDREW FRANK
• 金额: $ 8.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7509540
• 关键词: Affect; Antibodies; Binding; Biochemical; Biological Assay; Calcium Channel; Chromosome Pairing; Commit; Cyclin-Dependent Kinase 5; Data; Disease; Drosophila genus; Environment; Eph Family Receptors; EphA Receptors; EphA1 Receptor; Equilibrium; Faculty; Family; Fellowship; Fibroblast Growth Factor Receptors; Financial compensation; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Growth Cones; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Homologous Gene; Institution; Laboratories; Lead; Ligands; Link; Mediating; Mentors; Modeling; Molecular; Mutation; Nervous system structure; Neuromuscular Junction; Neurons; Neurophysiology - biologic function; Numbers; P-Q type voltage-dependent calcium channel; Pathway interactions; Phase; Play; Positioning Attribute; Protein Kinase C; Proteins; Public Health; Publishing; Reagent; Regulation; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Staining method; Stains; Structure; Synapses; Synaptic Transmission; System; Testing; Training; Vertebrates; Work; base; design; ephexin; interest; member; nervous system disorder; neuroregulation; neurotransmission; presynaptic; programs; relating to nervous system; research study; retinal rods; rho; rho GTP-Binding Proteins; src-Family Kinases; yeast two hybrid system

DESCRIPTION (provided by applicant): The causes and progression of several neurological diseases are influenced by factors that control the stability of neural function. Yet the mechanisms that dictate neural excitation and inhibition are poorly understood. Many studies indicate that homeostatic signaling mechanisms participate in the regulation of neural function - in paricular by modulating the strength of synaptic connections. This proposal aims to clarify the mechanisms of synaptic homeostatic signaling. Prior work defined a role for a presynaptic CaV2.1 calcium channel in synaptic homeostasis. New data show that the cytoplasmic signaling molecule, Ephexin, is also essential for synaptic homeostasis, and it may act via CaV2.1 regulation. In vertebrates, the Ephrin ligand and EphA receptor act upstream of Ephexin, and Rho-type GTPases act downstream of Ephexin to control growth cone dynamics. We hypothesize that all of these molecules are involved in a homeostatic signaling pathway in the presynaptic neuron. The proposed experiments for the K99 mentored phase will test this hypothesis. The results should define the role Ephexin signaling plays in the context of synaptic homeostasis. For the ROD independent phase, candidate molecules already known to regulate calcium channel function and Eph/Ephexin/GTPase signaling will be tested for roles in synaptic homeostasis. The long-term goal of this research is to define signaling mechisms with direct relevance to the cause and progression of neural disease. CANDIDATE: The K99 portion of this reserach will be conducted in the laboratory of Dr. Graeme W. Davis at UCSF. In this environment, I will continue to augment my training, both in the lab as well as in seminars, professional meetings, and one-on-one meetings with UCSF faculty. I am committed to attaining a faculty position at a major research institution. As an independent investigator, I would like to continue my research into the regulation of neural activity. PUBLIC HEALTH RELEVANCE: Many neurological diseases result from nervous system instability, but it is not understood exactly how neural stability is normally maintained. Data show that a molecule called Ephexin helps to direct neural stability. This proposal is designed to clarify exactly how Ephexin performs this function; the results may ultimately lead to a better understanding of the cause, progression, and treatment of neural diseases.

描述（由申请人提供）： 几种神经系统疾病的原因和进展受到控制神经功能稳定性的因素的影响。然而，对决定神经激发和抑制作用的机制知之甚少。许多研究表明，体内稳态信号传导机制参与了神经功能的调节 - 通过调节突触连接的强度，参与了神经功能的调节。该建议旨在阐明突触稳态信号传导的机制。 先前的工作定义了突触稳态中突触前CAV2.1钙通道的作用。新的数据表明，细胞质信号分子et ephecin对于突触稳态也是必不可少的，并且可以通过CAV2.1调节起作用。在脊椎动物中，以埃菲素的上游Ephrin配体和EPHA受体作用，而Rho-Type GTPases在以埃法蛋白的下游作用以控制生长锥体动力学。我们假设所有这些分子都参与突触前神经元中的稳态信号通路。 K99指导阶段提出的实验将检验该假设。结果应定义在突触稳态的背景下，以埃菲素信号的作用。对于杆独立阶段，将测试已经已知可以调节钙通道功能的候选分子和EPH/EPHENCIN/GTPase信号传导在突触稳态中的作用。这项研究的长期目标是定义与神经疾病的原因和进展直接相关的信号机电。候选人：本修复的K99部分将在UCSF的Graeme W. Davis博士实验室进行。在这种环境下，我将继续在实验室以及研讨会，专业会议和与UCSF教职员工的一对一会议上进行培训。我致力于在一家主要的研究机构获得教师职位。作为一名独立研究者，我想继续研究神经活动的调节。公共卫生相关性：许多神经疾病是由神经系统不稳定引起的，但尚不清楚通常如何维持神经稳定性。数据表明，一种称为赤行素的分子有助于指导神经稳定性。该提案旨在准确阐明以铁申请的执行方式。结果最终可能会更好地理解神经疾病的原因，进展和治疗。