The Influence and Regulation of Neuronal ROCK Signaling by IGF-1

 描述(申请人提供)：阿什波尔博士的长期职业目标是在老龄化领域，特别是神经科学领域，确立自己作为一名成功的、资金充足的独立研究员的地位。到目前为止，在她的培训生涯中，阿什波尔博士已经发表了12篇同行评议的出版物，成果丰硕。在她的博士培训中，她研究了神经细胞内的信号级联，为她目前的博士后工作奠定了坚实的基础 位置。为此，阿什波尔博士加入了威廉·桑塔格博士的实验室，研究依赖IGF-1的学习和记忆变化的潜在机制。桑塔格博士是神经内分泌信号和衰老领域的领先权威。桑塔格博士的实验室提供了多种活体方法，这将扩大她的技术技能，使她成为一名全面发展的研究科学家。这项建议中概述的研究战略将用于研究她博士培训中的信号级联的体外技术与桑塔格实验室的体内技术相结合。培训项目包括实验室培训、与桑塔格博士和一个咨询委员会的指导互动。总而言之，这一计划将确保阿什波尔博士过渡到老龄化领域的独立研究员。IGF-1的年龄依赖性缺失已被证明与认知功能障碍有关；然而，这种效应背后的病理生理学机制仍有待建立。这项拟议的研究将通过检测当IGF-1减少时可能导致神经元结构和功能变化的潜在信号通路来解决这一知识缺口。我们的初步数据表明，抑制IGF-1会导致Rho相关蛋白激酶(ROCK)的上调。阿什波尔博士假设，这种依赖于IGF-1的ROCK上调导致了与年龄相关的学习和记忆障碍，因为众所周知，RhoA/ROCK的活动会对神经元的结构和功能产生负面影响。为了更好地了解IGF-1调控的ROCK如何导致与年龄相关的认知能力下降，阿什波尔博士将首先研究IGF-1在特定目标1中调节岩石活动的机制。在特定目标2中，阿什波尔博士将研究IGF-1调控的ROCK对神经元结构的影响。最后，在具体目标3中，阿什波尔博士将通过测量小鼠模型中的长时程增强以及学习和记忆，研究IGF-1调控的ROCK如何影响神经元功能。虽然生长激素通常被认为仅仅是因为它们对细胞发育的贡献，但很明显，IGF-1在我们一生中维持神经元功能方面发挥着重要作用。因此，这项提案涉及在老龄化领域具有高度相关性的一个研究领域。已经提出的研究将探索当IGF-1在老年晚期减少时，导致认知障碍的新途径。正因为如此，该项目的发现可能会对改善老龄化人口的生活质量产生长期影响。

 DESCRIPTION (provided by applicant): The long-term career goal of Dr. Ashpole is to establish herself as a successful and well-funded, independent investigator in the field of aging, and in particular, the area of neuroscience. Thus far in her training career, Dr. Ashpole has been highly-productive with 12 peer-reviewed publications. Her doctoral training, in which she studied intracellular signaling cascades in neurons, laid a strong foundation for her current post-doctoral position. For this, Dr. Ashpole joined the laboratory of Dr. William Sonntag to study the mechanisms underlying IGF-1-dependent changes in learning and memory. Dr. Sonntag is a leading authority in the field of neuroendocrine signaling and aging. Dr. Sonntag's laboratory offers a variety of in vivo approaches which will expand her technique repertoire and allow her to become a well-rounded research scientist. The research strategy outlined in this proposal incorporates the in vitro techniques used to study signaling cascades from her doctoral training with the in vivo techniques in the Sonntag laboratory. The training program includes a mixture of laboratory training and mentoring interactions with Dr. Sonntag and an advisory council. Together, this program will ensure the Dr. Ashpole transitions to an independent investigator in the field of aging. The age-dependent loss of IGF-1 has been shown to contribute to cognitive impairment; however, the pathophysiological mechanisms underlying this effect remain to be established. The proposed studies will address this gap in knowledge by examining potential signaling pathways that may induce changes in neuronal structure and function when IGF-1 is reduced. Our preliminary data indicates that IGF-1 inhibition leads to the upregulation of the Rho-associated protein kinase (ROCK). Dr. Ashpole hypothesizes that this IGF-1- dependent upregulation of ROCK contributes to age-related impairments in learning and memory, as RhoA/ROCK activity is known to negatively influence neuronal structure and function. To better understand how IGF-1-regulated ROCK contributes to age-related cognitive decline, Dr. Ashpole will first examine the mechanisms by which IGF-1 regulates ROCK activity in Specific Aim 1. In Specific Aim 2, Dr. Ashpole will examine the effects of IGF-1-regulated ROCK on neuronal structure. Finally, in Specific Aim 3, Dr. Ashpole will examine how IGF-1-regulated ROCK influences neuronal function by measuring long-term potentiation as well as learning and memory within our mouse models. While growth hormones are often recognized solely for their contribution to cell development, it is obvious that IGF-1 plays an important role in maintaining neuronal function throughout our lifetime. Thus, this proposal addresses an area of research that is of high relevance in the field of aging. The studies that have been proposed will explore novel pathways that contribute to cognitive impairment when IGF-1 is reduced in advanced aging. Because of this, findings from this project may have long-term implications in improving the quality of life in the aging population.