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

项目摘要/摘要 这个项目的长期目标是将洛根博士建立成一个成功的、有资金的、独立的 在衰老领域，特别是线粒体氧化还原动态平衡和脑老化领域的研究员。洛根博士 加入威廉·桑塔格博士的实验室，研究IGF-1依赖改变的机制 学习和记忆。桑塔格博士是神经内分泌信号和衰老领域的领先权威。Dr。 桑塔格的实验室提供了多种活体方法，这将扩大她的技术储备，并允许 她想成为一名全面发展的研究科学家。概述的研究策略结合了体外技术。 用于在桑塔格实验室用活体技术研究线粒体代谢。培训 该计划包括实验室实践培训、杂志俱乐部和与Dr。 范·雷曼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培训 在线粒体功能和信号网络中直接相关的这一领域的研究。这一计划将 确保洛根博士过渡到衰老研究领域的独立研究员。短期内 此应用程序的目的是增强应聘者对线粒体代谢和氧化还原的知识 动态平衡和长期性，使应聘者作为一名新聘用的教员，能够确保受保护的时间 对于研究活动，建立新的合作，并追求一条新的独立研究路线，以产生 在竞争性拨款提案中。洛根博士的初步数据表明，IGF-1调节能量 星形胶质细胞而不是神经元中的水平；IGF-1信号的丢失减少了星形胶质细胞的能量电荷，增加了 线粒体ROS在长期维持时会导致学习和记忆损伤。这项建议 扩展了这些新发现，以更好地理解IGF-1如何调节线粒体生物能量学和氧化还原 信号传递导致了与年龄相关的认知能力下降。最重要的假设是星形细胞的像差 随着年龄的增长，氧化还原和能量平衡会导致认知缺陷。提出了以下目标：1) 确定IGF-1R信号缺陷是否损害星形胶质细胞线粒体功能和生物能量学；2) 破译IGF-1R信号缺陷星形胶质细胞氧化还原动态平衡的分子调控； 描述星形胶质细胞中IGF-1R信号对学习和记忆的功能影响。这些研究 将探索增加神经退行性疾病风险的途径，有助于 这可能会导致认知障碍，并有可能成为改善老年人生活质量的目标。

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.