How Ephexin Signaling Promotes Neuronal Stability

描述(由申请人提供)： 一些神经系统疾病的发生和发展受到控制神经功能稳定性的因素的影响。然而，人们对神经兴奋和抑制的机制知之甚少。许多研究表明，动态平衡信号机制通过调节突触连接的强度参与神经功能的调节。这项建议旨在阐明突触内稳态信号的机制。先前的工作明确了突触前CaV2.1钙通道在突触内稳态中的作用。新的数据表明，胞质信号分子Ephexin也是突触动态平衡所必需的，它可能通过CaV2.1调节发挥作用。在脊椎动物中，EPhin配体和EphA受体作用于Ephexin的上游，而Rho类型的GTP酶作用于Ephexin的下游，以控制生长锥的动态。我们假设所有这些分子都参与了突触前神经元的动态平衡信号通路。K99指导阶段的拟议实验将检验这一假设。这一结果应该能明确Ephexin信号在突触内稳态中所起的作用。对于Rod非依赖性阶段，已知的调节钙通道功能和Eph/Ephexin/GTPase信号的候选分子将被测试在突触内稳态中的作用。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制。候选人：这项研究的K99部分将在加州大学旧金山分校的Graeme W.Davis博士的实验室进行。在这种环境下，我将继续加强我的培训，无论是在实验室还是在研讨会、专业会议和与加州大学旧金山分校教职员工的一对一会议中。我致力于在一家大型研究机构获得教职。作为一名独立的研究员，我想继续我对神经活动调节的研究。公共卫生相关性：许多神经系统疾病是由神经系统不稳定引起的，但人们并不确切地了解正常情况下神经稳定性是如何维持的。数据显示，一种名为Ephexin的分子有助于指导神经稳定性。这项建议旨在明确Ephexin是如何执行这一功能的；结果可能最终会导致更好地理解神经疾病的病因、进展和治疗。

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.