IGF-1 Regulation of Astrocyte Mitochondrial Metabolism and Redox Homeostasis in Brain Aging

项目总结/摘要 这个项目的长期目标是建立洛根博士作为一个成功的和资助，独立 他是衰老领域的研究者，特别是线粒体氧化还原稳态和脑衰老。罗根医生 加入了威廉·桑塔格博士的实验室，研究IGF-1依赖性变化的机制， 学习和记忆。Sonntag博士是神经内分泌信号和衰老领域的权威。博士 Sonntag的实验室提供了多种体内方法，这将扩大她的技术储备， 使她成为一名全面的研究科学家。概述的研究策略包括体外技术 用于在Sonntag实验室用体内技术研究线粒体代谢。培训 该计划包括动手实验室培训，期刊俱乐部和指导与博士互动的混合物。 货车雷门和俄克拉荷马州内森休克中心的成员。洛根博士将接受专门的训练 在线粒体功能和信号网络直接相关的这一领域的研究。此程序将 确保洛根博士过渡到一个独立的调查员在老龄化研究领域。短期 本申请的目的是提高考生对线粒体代谢和氧化还原的认识 稳态和长期，使候选人，作为一个新雇用的教师，以确保保护时间 对于研究活动，建立新的合作，并追求一种新的独立研究路线， 在竞争性的拨款申请中。洛根博士的初步数据表明，IGF-1调节能量 水平，而不是神经元; IGF-1信号的损失减少了星形胶质细胞的能量电荷，增加了 线粒体活性氧，当长期持续导致学习和记忆障碍。这项建议 扩展了这些新的发现，以更好地了解IGF-1如何调节线粒体生物能量学和氧化还原 信号传导导致与年龄相关的认知能力下降。总体假设是星形胶质细胞的畸变 氧化还原和能量稳态导致认知缺陷随年龄增长。提出了以下目标：1） 确定IGF-1 R信号传导缺陷是否损害星形胶质细胞线粒体功能和生物能量学; 2） 解读IGF-1 R信号转导缺陷星形胶质细胞中氧化还原稳态的分子调节;以及3） 描述星形胶质细胞中IGF-1 R信号对学习和记忆的功能影响。研究 已经提出的将探索增加神经退行性疾病风险的途径， 认知障碍，并可能有针对性地改善老年人的生活质量。

PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to establish Dr. Logan as a successful and funded, independent investigator in the field of aging, and in particular, mitochondrial redox homeostasis and brain aging. Dr. Logan 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 technical repertoire and allow her to become a well-rounded research scientist. The research strategy outlined incorporates in vitro techniques used to study mitochondrial metabolism with the in vivo techniques in the Sonntag laboratory. The training program includes a mixture of hands-on laboratory training, journal clubs and mentoring interactions with Dr. Van Remmen and members of the Oklahoma Nathan Shock Center. Dr. Logan will receive specialized training in mitochondrial function and signaling networks directly relevant to this area of research. This program will ensure that Dr. Logan transitions to an independent investigator in the field of aging research. The short-term objective of this application is to enhance the candidate's knowledge of mitochondrial metabolism and redox homeostasis and long-term to enable the candidate, as a newly-hired faculty member, to secure protected time for research activity, establish new collaborations, and pursue a novel line of independent research that results in competitive grant proposals. Preliminary data performed by Dr. Logan indicate that IGF-1 regulates energy levels in astrocytes rather than neurons; loss of IGF-1 signaling reduces energy charge in astrocytes, increases mitochondrial ROS that when chronically sustained leads to learning and memory impairments. This proposal expands these novel findings to better understand how IGF-1-regulated mitochondrial bioenergetics and redox signaling contribute to age-related cognitive decline. The overarching hypothesis is that aberrations in astrocytic redox and energy homeostasis contribute to cognitive deficits with age. The following aims are proposed: 1) Determine whether IGF-1R signaling deficiency impairs astrocyte mitochondrial function and bioenergetics; 2) Decipher the molecular regulation of redox homeostasis in astrocytes with IGF-1R signaling deficiency; and 3) Delineate the functional consequence of IGF-1R signaling in astrocytes on learning and memory. The studies that have been proposed will explore pathways that increase the risk for neurodegenerative disease, contribute to cognitive impairment and potentially be targeted to improve the quality of life for older individuals.