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

IGF-1 对星形胶质细胞线粒体代谢和脑衰老过程中氧化还原稳态的调节

基本信息

批准号：
10462512
负责人：
Sreemathi Logan
金额：
$ 24.9万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462512
关键词：
Address Age Age-associated memory impairment Aging Animals Antioxidants Applications Grants Area Astrocytes Behavior assessment Bioenergetics Blood Vessels Brain Cells Charge Chronic Cognition Cognitive Cognitive Therapy Cognitive deficits Collaborations Data Disease Electron Transport Energy Metabolism Ensure Faculty Functional disorder Funding Gene Expression Genus Hippocampus Glial Fibrillary Acidic Protein Goals Growth Factor Health Hippocampus (Brain)Homeostasis Human Impaired cognition Impairment In Vitro Incidence Individual Injections Journals Knock-out Knockout Mice Knowledge Laboratories Learning Long-Term Potentiation MAPK8 gene Maintenance Malignant Neoplasms Measurement Memory Memory impairment Mentors Metabolic Mitochondria Modeling Molecular Mus NF-kappa B Neurodegenerative Disorders Neurons Neurosecretory Systems Oklahoma Oxidation-Reduction Oxidative Regulation Oxidative Stress Oxygen Consumption Pathway interactions Pharmacology Production Quality of life Reactive Oxygen Species Regulation Reporting Research Research Activity Research Personnel Risk Role Scientist Secure Series Shock Signal Pathway Signal Transduction Somatomedins Stress Techniques Testing Therapeutic Intervention Time Tissues Training Training Programs Traumatic Brain Injury age related age related neurodegeneration aged aging brain authority brain health brain tissue cell type cognitive function cognitive reappraisal experimental study gain of function improved in vivo insulin-like signaling knock-down laboratory experience loss of function member metabolomics mitochondrial metabolism neuron loss novel overexpression oxidative damage prevent programs response targeted treatment therapeutic target

项目摘要

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.

项目概要/摘要该项目的长期目标是将洛根博士打造成一个成功的、有资金支持的、独立的衰老领域，特别是线粒体氧化还原稳态和脑衰老领域的研究人员。洛根博士加入 William Sonntag 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传导和衰老领域的权威。博士。 Sonntag 的实验室提供了多种体内方法，这将扩展她的技术库并允许她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 Sonntag 实验室通过体内技术研究线粒体代谢。培训内容计划包括实验室实践培训、期刊俱乐部以及与 Dr. 的指导互动。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培训与该研究领域直接相关的线粒体功能和信号网络。该计划将确保洛根博士转变为衰老研究领域的独立研究者。短期此应用程序的目的是增强考生对线粒体代谢和氧化还原的了解稳态和长期，使候选人作为新聘的教员能够获得受保护的时间对于研究活动，建立新的合作，并追求新的独立研究路线，从而产生在竞争性拨款提案中。 Logan 博士进行的初步数据表明 IGF-1 调节能量星形胶质细胞而不是神经元中的水平； IGF-1 信号传导的丧失会减少星形胶质细胞的能量电荷，增加线粒体活性氧长期持续会导致学习和记忆障碍。这个提议扩展了这些新发现，以更好地了解 IGF-1 如何调节线粒体生物能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随着年龄的增长，氧化还原和能量稳态会导致认知缺陷。提出以下目标：1) 确定 IGF-1R 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学； 2）破译 IGF-1R 信号缺陷星形胶质细胞氧化还原稳态的分子调节；和 3) 描述星形胶质细胞中 IGF-1R 信号传导对学习和记忆的功能影响。研究已提出的将探索增加神经退行性疾病风险的途径，有助于认知障碍，并可能旨在改善老年人的生活质量。