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

IGF-1 对神经元 ROCK 信号传导的影响和调节

• 批准号: 8832449
• 负责人: Nicole M Ashpole
• 金额: $ 5.33万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832449
• 关键词: Address; Age; Age-associated memory impairment; Aging; Animal Model; Animals; Area; Behavioral; Biological Assay; Brain; Caregivers; Cells; Cognition; Cognitive deficits; Data; Development; Elderly; Ensure; Environment; Etiology; Foundations; Funding; Goals; Growth; Growth Factor; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Insulin-Like Growth Factor I; Investigation; Knowledge; Laboratories; Lead; Learning; Long-Term Potentiation; Maintenance; Measures; Memory; Mentors; Molecular; Mus; Neurites; Neuronal Differentiation; Neuronal Plasticity; Neurons; Neurosciences; Neurosecretory Systems; Pathway interactions; Patients; Peer Review; Phosphotransferases; Play; Positioning Attribute; Postdoctoral Fellow; Protein Kinase; Publications; Quality of life; Rattus; Regulation; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Somatotropin; Structure; Supplementation; Synapses; Synaptic plasticity; Techniques; Training; Training Programs; Up-Regulation; Vertebral column; age related; aged; aging population; authority; base; career; experience; improved; in vivo; interest; member; mouse model; neurofilament; neuronal growth; novel; programs; public health relevance; research study; rho; therapeutic target

 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.

 Ashpole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，成为一名成功的、资金充足的独立研究者。到目前为止，在她的培训生涯中，Ashpole博士已经有12篇同行评审的出版物。她的博士培训，她研究了神经元的细胞内信号级联，为她目前的博士后奠定了坚实的基础 位置为此，Ashpole博士加入了William Sonntag博士的实验室，研究学习和记忆中IGF-1依赖性变化的机制。Sonntag博士是神经内分泌信号和衰老领域的权威。Sonntag博士的实验室提供了各种体内方法，这将扩大她的技术库，使她成为一个全面的研究科学家。本提案中概述的研究策略结合了Sonntag实验室博士培训中用于研究信号级联的体外技术和体内技术。培训计划包括实验室培训和与Sonntag博士和咨询理事会的指导互动。总之，该计划将确保Ashpole博士过渡到老龄化领域的独立调查员。IGF-1的年龄依赖性损失已被证明有助于认知障碍;然而，这种影响的病理生理机制仍有待建立。拟议的研究将通过检查可能在IGF-1减少时诱导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，IGF-1抑制导致Rho相关蛋白激酶（ROCK）的上调。Ashpole博士假设，这种IGF-1依赖性的ROCK上调有助于与年龄相关的学习和记忆障碍，因为已知RhoA/ROCK活性会对神经元结构和功能产生负面影响。为了更好地了解IGF-1调节的ROCK如何导致与年龄相关的认知能力下降，Ashpole博士将首先研究IGF-1调节特定目标1中ROCK活性的机制。在具体目标2中，Ashpole博士将研究IGF-1调节的ROCK对神经元结构的影响。最后，在具体目标3中，Ashpole博士将通过测量长时程增强以及我们小鼠模型中的学习和记忆来研究IGF-1调节的ROCK如何影响神经元功能。 虽然生长激素通常仅因其对细胞发育的贡献而被认可，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，本提案涉及与老龄化领域高度相关的一个研究领域。已经提出的研究将探索当IGF-1在晚期衰老中减少时导致认知障碍的新途径。因此，该项目的研究结果可能对改善老龄人口的生活质量具有长期影响。