'REGULATORY MECHANISMS OF KALIRIN'S GEF1 DOMAIN'

描述（由申请人提供）： 了解神经元如何启动神经突生长很重要，这不仅仅是为了 我们对神经系统和神经元发育的基本认识 形态学，但也有助于发展神经系统疾病的治疗方法。 紊乱我的长期目标是了解 鸟嘌呤核苷酸交换因子和GTP酶调节神经元形态， 作为使用Kalirin帮助神经元再生发展的基础 战略布局这个RCDA的目标是让我获得额外的 专业知识，培养学术科学家所需的几项技能， 在一个新的研究领域发展历史，并开始建立一个新的 研究计划。在这一建议的过程中， 议程将包括参加和运行期刊俱乐部，发表演讲， 上课，授课和接受高质量的指导，以满足 这些发展目标。我将在多维核磁共振指导博士。 Glenn King，一位具有出色生产力的核磁共振波谱专家 记录贝蒂·艾珀博士将帮助我培养管理一个 新实验室，授课，培训员工。艾珀博士做了很多 对神经肽领域的开创性贡献， 培养未来的科学领袖几项研究和我们的初步 实验表明Kalirin在神经突形成中起关键作用， 神经元分化考虑到孤立卡林的鲁棒效应， GEF1结构域对神经元发育的影响，本提案的目标是更好地 了解完整卡林的GEF1结构域的机制 监管.我们将首先确定调节细胞凋亡的kalirin的结构域。 通过产生一系列突变缺失kalirin蛋白和 在神经突生长和GEF激活试验中测试它们。使用 从这些实验中获得的信息，我们将追求几个之一 确定的监管领域可能控制的潜在机制 GEF1结构域。最后，机械假说将进一步完善， 在分子水平上用核磁共振确定三维结构 GEF 1及其调控元件的作用，并检查配体的作用 结构上的相互作用。了解环境基金 控制Kalirin的结构域将为未来的研究提供基础， 确定kalirin控制神经元形态的机制。

DESCRIPTION (provided by applicant): Understanding how neurons initiate neurite outgrowth is important, not just for our basic understanding of development of the nervous system and neuronal morphology, but also to aid in the development of therapies for neurological disorders. My long-term goal is to understand the molecular mechanisms by which guanine nucleotide exchange factors and GTPases modulate neuronal morphology, as a basis for using Kalirin to aid in the development of neuronal regeneration strategies. The goal of this RCDA is to allow me to obtain additional expertise, cultivate several of the skills necessary for an academic scientist, develop a history in a new field of study, and begin to establish a new research program. During the course of this proposal a multifaceted development agenda will involve attending and running journal clubs, giving presentations, taking classes, teaching classes and receiving high-quality mentorship to meet these developmental goals. I will be mentored in multidimensional NMR by Dr. Glenn King, an expert NMR spectroscopist with an outstanding productivity record. Dr. Betty Eipper will help me cultivate the skills needed to manage a new laboratory, teach classes, and train staff. Dr. Eipper has made many seminal contributions to the neuropeptide field and has a long-history of training future leaders in science. Several studies and our preliminary experiments indicate that Kalirin plays a key role in neurite formation and neuronal differentiation. Considering the robust effect of the isolated kalirin GEF1 domain on neuronal development, the goal of this proposal is to better understand the mechanism(s) by which the GEF1 domain of intact kalirin is regulated. We will first identify the domain(s) of kalirin that regulate the GEF1 domain by generating a series of mutant deletion kalirin proteins and testing them in neurite outgrowth and GEF activation assays. Using the information gained from these experiments, we will pursue one of several potential mechanisms by which the identified regulatory domain might control the GEF1 domain. Finally, the mechanistic hypotheses will be further refined at the molecular level by using NMR to determine the three-dimensional structure of the GEF1 with its regulatory elements and examining the effects of ligand interactions upon the structure. Understanding the mechanism by which the GEF domain of kalirin is controlled will provide a basis for future studies to determine the mechanisms by which kalirin controls neuronal morphology.