Systemic Mechanisms of Brain Rejuvenation

大脑年轻化的系统机制

基本信息

批准号：
10467545
负责人：
SAUL A VILLEDA
金额：
$ 55.92万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467545
关键词：
Adult Alzheimer&apos s Disease Alzheimer&apos s disease model Animals Attenuated Biological Assay Blood Blood - brain barrier anatomy Blood Circulation Blood Platelets Brain Cardiovascular system Cells Coagulation Process Cognition Cognitive Data Dementia Disease Elderly Exercise Exposure to Hippocampus (Brain)Immune Impaired cognition Impairment In Vitro Incidence Learning Mass Spectrum Analysis Mediating Memory Microglia Molecular Mus Neurodegenerative Disorders PF4 Gene Parabiosis Pathway interactions Peripheral Plasma Proteomics Regenerative capacity Regulation Rejuvenation Research Role Testing Therapeutic Therapeutic Effect Walkers adult neurogenesis age related age related neurodegeneration age related neuroinflammation aged aging brain aging hippocampus behavior test chemokine cognitive benefits cognitive function immunoregulation improved in vivo insight mouse model neurodegenerative phenotype neurogenesis neuroinflammation new therapeutic target novel therapeutics regenerative single-cell RNA sequencing systemic intervention theories therapeutic candidate therapeutic target trafficking translational potential

项目摘要

PROJECT SUMMARY/ABSTRACT The ability to enhance cognition by targeting circulating factors in the systemic milieu provides a unique and underexplored therapeutic approach to brain aging. We and others have shown that systemic manipulations, including exposure to young blood through heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) and young blood plasma administration, revitalize the aged hippocampus and ameliorate cognitive decline in aged mice. The rejuvenating effects of young blood mirror those observed with exercise, positing common bloodborne mechanisms of action by which broad systemic interventions exert their beneficial effects. Preliminary data from our labs indicate that systemic administration of platelet factors derived from either naïve young mice or exercised mice reverses age-related impairments in adult neurogenesis, deceases neuroinflammation and restores cognitive function in aged mice. Moreover, using proteomics, our two groups have independently identified CXCL4/platelet factor 4 (PF4)—a chemokine released from platelets, involved in coagulation and a variety of immunomodulatory functions—as a potential young blood-derived and exercise-induced anti-geronic circulating factor. The proposed study will investigate the rejuvenating and therapeutic effects of platelet factors on the aged brain. Specifically, our hypothesis is that systemic exposure to platelet factors rejuvenates adult neurogenesis, attenuates neuroinflammation and improves cognition, while ameliorating neurodegenerative phenotypes. We will test this theory with three specific aims: 1: Determine mechanisms downstream of PF4 underlying cognitive and regenerative rejuvenation in the aged hippocampus. 2: Examine the rejuvenating effects of PF4 on neuroinflammation in the aged hippocampus. 3: Investigate the beneficial effects of PF4 in a mouse model of Alzheimer’s disease. Successful completion of these studies will have significant translational potential, identifying platelet-derived circulating factors as candidate therapeutic targets to restore age-related cognitive dysfunction and potentially treat dementia-related neurodegenerative disorders such as Alzheimer’s disease.

项目概要/摘要通过针对系统环境中的循环因子来增强认知的能力提供了独特且我们和其他人已经表明，系统性操作，包括通过异时性联体共生（其中年轻人的循环系统和老年动物加入）和年轻血浆给药，使衰老的海马体恢复活力，改善老年小鼠的认知能力下降，年轻血液的恢复效果与用小鼠血液观察到的效果相似。运动，提出了共同的血源性作用机制，通过该机制广泛的系统干预措施发挥其作用我们实验室的初步数据表明，血小板因子的全身给药产生了有益的效果。来自幼年幼鼠或锻炼过的小鼠的研究可以逆转成年神经发生中与年龄相关的损伤，减少老年小鼠的神经炎症并恢复认知功能此外，我们的两个研究人员利用蛋白质组学进行了研究。研究小组独立鉴定了 CXCL4/血小板因子 4 (PF4)——一种从血小板释放的趋化因子，参与凝血和多种免疫调节功能——作为一种潜在的年轻血液来源和运动诱发的抗衰老循环因子。具体来说，我们的假设是血小板因子对老年大脑的治疗作用。血小板因子可以使成人神经发生恢复活力，减轻神经炎症并改善认知能力，同时我们将通过三个具体目标来检验这一理论： 1：确定 PF4 的下游机制是老年海马认知和再生再生的基础。 2：检查 PF4 对衰老海马神经炎症的恢复作用。 3：研究 PF4 对阿尔茨海默病小鼠模型的有益作用将成功完成这些研究。具有显着的转化潜力，将血小板衍生的循环因子确定为候选治疗药物目标是恢复与年龄相关的认知功能障碍，并可能治疗痴呆相关的神经退行性疾病阿尔茨海默病等疾病。