Pro-youthful role of Gpld1 on regenerative and cognitive function in the aged brain

Gpld1 对老年大脑再生和认知功能的促年轻作用

• 批准号: 10621267
• 负责人: SAUL A VILLEDA
• 金额: $ 63.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621267
• 关键词: Adherence; Adult; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Animal Model; Animals; Antisense Oligonucleotides; Behavioral Paradigm; Bioluminescence; Blood; Brain; Cardiovascular system; Cognition; Confocal Microscopy; Data; Dementia; Dioxygenases; Disease; Elderly; Epigenetic Process; Exercise; Genetic; Glycosylphosphatidylinositols; Health; Hippocampus; Human; Immunohistochemistry; Impaired cognition; Impairment; Incidence; Individual; Kinetics; Knockout Mice; Knowledge; Learning; Light; Liver; Mediating; Memory; Molecular; Mus; Neurodegenerative Disorders; Parabiosis; Pathway interactions; Perception; Plasma; Population; Predisposition; Process; RNA Interference; Radial; Regenerative capacity; Rejuvenation; Research; Role; Running; Testing; Therapeutic; Up-Regulation; Viral; adult neurogenesis; age effect; age related; age related neurodegeneration; aged; aging brain; aging hippocampus; arm; cognitive benefits; cognitive function; cognitive process; combat; conditioned fear; fitness; frailty; hippocampal atrophy; improved; in vivo; insight; liver function; mouse model; neurogenesis; new therapeutic target; novel therapeutics; phospholipase D1; regeneration function; regenerative; sedentary; theories; transcriptome sequencing; translational potential; water maze

PROJECT SUMMARY/ABSTRACT Identifying novel therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing elderly population. Exercise has been shown to rejuvenate regenerative capacity and cognition in the aged brain in animal models. Moreover, exercise has been shown to improve learning and memory in Alzheimer’s disease patients. Excitingly, our lab recently demonstrated that systemic administration of blood plasma derived from exercised mice reverses age- related impairments in adult neurogenesis and cognition in aged mice. We identify glycosylphosphatidylinositol specific phospholipase D1 (Gpld1) as a liver-derived exercise blood factor – the plasma levels of which correlate with improved cognitive function in aged mice, and the levels of which are increased in active healthy elderly humans. Functionally, we show that increasing liver-derived systemic Gpld1 in aged mice ameliorates age- related regenerative and cognitive impairments. These data raise fundamental questions as to the function of liver-derived systemic Gpld1: How long lasting are the rejuvenating effects of systemic Gpld1 on the aged brain? What is the role of systemic Gpld1 in mediating the rejuvenating effects of exercise on the aged brain? 3. What molecular mechanisms underly the rejuvenating effects of systemic Gpld1 in the aged brain? The purpose of the proposed study is to investigate the rejuvenating effects of systemic Gpld1 on the aged brain. Specifically, our hypothesis is that exercise-induced liver-derived systemic Gpld1 elicits long lasting rejuvenation of regenerative and cognitive functions in the aged hippocampus. We will test this theory with Three Specific Aims: 1: Characterize the kinetics of brain rejuvenation following increased liver-derived systemic Gpld1. 2: Investigate the necessity of exercise-induced systemic Gpld1 in mediating the rejuvenating effects of exercise on the aged brain. 3: Determine molecular mechanisms underlying the rejuvenating effects of liver-derived systemic Gpld1 in the aged brain. Successful completion of these studies will have significant translational potential, revealing pathways that could be targeted for novel therapies to ameliorate age-related neurodegenerative diseases such as Alzheimer’s disease.

项目摘要/摘要 确定新的治疗方法来延迟并可能逆转与年龄相关的认知能力下降至关重要， 在不断增长的老年人口中，预计痴呆症相关疾病的发病率会增加。演习 在动物模型中显示出恢复老年大脑的再生能力和认知能力。此外，委员会认为， 运动已被证明可以改善阿尔茨海默病患者的学习和记忆。令人兴奋的是，我们的实验室 最近证明，全身施用来自运动小鼠的血浆可逆转年龄， 成年神经发生和老年小鼠认知的相关损伤。我们鉴定了糖基磷脂酰肌醇 特异性磷脂酶D1（Gpld 1）作为肝源性运动血液因子-其血浆水平与 在老年小鼠中具有改善的认知功能，并且其水平在活跃的健康老年人中增加 人类从功能上讲，我们发现增加老年小鼠肝源性全身Gpld 1可以改善年龄相关性。 相关的再生和认知障碍。这些数据提出了一些基本问题， 肝源性全身性Gpld 1：全身性Gpld 1对老年大脑的恢复作用持续多久？ 系统性Gpld 1在介导运动对老年大脑的恢复活力作用中的作用是什么？3.什么 系统性Gpld 1在老年大脑中的返老还童作用的分子机制？的目的 提出的研究是调查系统性Gpld 1对老年大脑的返老还童作用。具体来说，我们 假设是运动诱导肝源性全身性Gpld 1促进再生神经元的持久再生， 以及老年海马体的认知功能。我们将用三个具体目标来测试这个理论：1： 表征肝源性全身性Gpld 1增加后脑年轻化的动力学。2：调查 运动诱导的系统性Gpld 1在介导运动对老年人的返老还童效应中的必要性 个脑袋3：确定肝源性全身性Gpld 1在小鼠中的再生作用的分子机制。 大脑老化成功完成这些研究将具有重大的翻译潜力， 这些途径可以作为新疗法的靶点，以改善与年龄相关的神经退行性疾病， 老年痴呆症