NOVEL CHEMICAL-GENETIC APPROACHES TO MEMORY FORMATION

描述：我们研究的长期目标是阐明分子 以及哺乳动物大脑中学习和记忆的细胞机制。建房 论脑区特异性基因成功开发的力量 击穿技术，我们建议探索一种新颖的撞击和空穴 研究快速(秒-分钟)信号的化学遗传学方法 不同蛋白激酶控制的级联反应及其在体内的功能 哺乳动物大脑中的学习和记忆。这种新的化学成因 方法有两个强大的应用程序：第一，它可以用来开发 第三代基因敲除技术，它结合了 分子遗传学与药理学的可逆、快速动力学。这 基于化学物质的基因敲除技术应该允许更精确的分子 蛋白激酶在不同时间阶段中的作用剖析 学习和记忆巩固。其次，这种新颖的碰撞和洞穴方法 也提供了前所未有的机会来确定直接的底物 不同的激酶，这是一项具有挑战性的任务，到目前为止，由于 蛋白激酶家族和极其保守的蛋白激酶结构域。 在这个提案中，我们将集中在两个主要的神经激酶上来演示 这一新方法具有广泛的实用性。第一套生化和生物化学 将进行分子实验，以系统地进行鉴定和分析 它们的直接下游底物。第二组遗传和行为 将进行实验，以证明该方案的可行性 化学遗传学方法研究记忆巩固。理解 在记忆形成中，激酶触发的分子级联事件可能导致 记忆治疗中潜在治疗干预的新策略 阿尔茨海默氏症等疾病。

DESCRIPTION: The long-term goals of our research are to elucidate the molecular and cellular mechanisms of learning and memory in the mammalian brain. Building on the strength of the successful development of brain region-specific gene knockout technology, we propose to explore a novel bump-and-hole chemical-genetic approach for the study of rapid (seconds-minutes) signaling cascades controlled by various protein kinases and of their functions in learning and memory in the mammalian brain. This novel chemical-genetic approach has two powerful applications: First, it can be used to develop the third-generation gene knockout technology, which combines the specificity of molecular genetics with the reversible, fast kinetics of pharmacology. This chemical based gene knockout technique should permit more precise molecular dissections of the roles of protein kinases in various temporal stages of learning and memory consolidation. Secondly, this novel bump-and-hole approach also offers the unprecedented opportunity to identify the direct substrates of the various kinases, a challenging task so far hindered by complexity of the kinase family and extremely conserved kinase domains. In this proposal, we will focus on two major neural kinases to demonstrate the broad utility of this novel approach. The first set of biochemical and molecular experiments will be performed to systemically identify and analyze their direct downstream substrates. The second set of genetic and behavioral experiments will be carried out to demonstrate the feasibility of the chemical-genetic approach to the study of memory consolidation. Understanding the kinase-triggered molecular cascade events in memory formation may lead to a new strategy for potential therapeutic interventions in the treatment of memory disorders such as Alzheimer's disease.