Investigating the pro-aging role of B2M and MHC molecules on regenerative and cognitive function in the brain

研究 B2M 和 MHC 分子对大脑再生和认知功能的促衰老作用

• 批准号: 10112790
• 负责人: SAUL A VILLEDA
• 金额: $ 32.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112790
• 关键词: Address; Adult; Affect; Aging; Animals; Automobile Driving; Behavioral Paradigm; Biological; Bioluminescence; Blood; Brain; Candidate Disease Gene; Cardiovascular system; Cell surface; Cognition; Cognitive; Data; Dementia; Elderly; Environment; Event; Exposure to; Faculty; Genetic; Goals; Hippocampus (Brain); Histocompatibility Antigens Class I; Impaired cognition; Impairment; In Vitro; Individual; Investigation; Knock-out; Knockout Mice; Mediating; Modeling; Molecular; Mus; Neurodegenerative Disorders; Parabiosis; Pathway interactions; Phenotype; Plasma; Predisposition; Process; RNA Interference; Regenerative capacity; Rejuvenation; Reporting; Research; Role; Testing; Therapeutic; Virus; Work; adult neurogenesis; age effect; age related; aged; aging brain; anti aging; beta-2 Microglobulin; cognitive enhancement; cognitive function; effectiveness evaluation; human old age (65+); in vivo; insight; juvenile animal; mouse model; neurogenesis; new therapeutic target; normal aging; overexpression; prevent; regeneration function; regenerative; relating to nervous system; stem; stem cell function; stem cells; theories; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Aging drives regenerative and cognitive impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. One exciting possibility is to harness the regenerative capacity of stem cells in the adult brain to reverse normal aging and ameliorate cognitive dysfunction by enhancing neurogenesis. We, and others, have shown that systemic manipulations such as heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) or young plasma administration can partially reverse age-related impairments in neural stem/progenitor cell (NPC) function and loss of cognitive faculties in the aged brain. Interestingly, heterochronic parabiosis studies have revealed an age-dependent bi-directionality in the influence of the systemic environment indicating anti-aging factors in young blood elicit rejuvenation while pro-aging factors in old blood drive aging. It has been proposed that mitigating the effect of pro-aging factors may also provide an effective approach to rejuvenate aging phenotypes, however functional investigation of individual pro-aging factors is lacking. Recently my lab identified β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a systemic pro-aging factor that negatively regulates regenerative and cognitive functions in the adult hippocampus. The purpose of the proposed study is to gain mechanistic insight into the pro-aging effects of MHC I molecules on the aging brain, and ascertain the therapeutic potential of targeting these molecules at old age. Specifically, our hypothesis is that B2M in concert with classical MHC I molecules act as pro-aging factors driving age-related regenerative and cognitive impairments in the adult hippocampus. We will test this theory with Three Specific Aims: 1: Characterize age-related molecular mechanisms downstream of B2M and MHC I underlying regenerative and cognitive enhancements in the adult brain. 2: Determine effectiveness of reducing cell surface MHC I expression to ameliorate age-related regenerative and cognitive impairments. 3: Investigate classical MHC I molecules, H2-Kd and H2-Db, as pro-aging negative regulators of regenerative and cognitive function in the brain. Successful completion of these studies will have significant translational potential, identifying molecular pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative disorders and their downstream consequences in terms of impaired regenerative and cognitive functions.

项目概要/摘要 衰老会导致成人大脑的再生和认知障碍，增加对 健康个体的神经退行性疾病的一种令人兴奋的可能性是利用再生能力。 成人大脑中的干细胞具有逆转正常衰老和改善认知功能障碍的能力 我们和其他人已经证明了系统性操作，例如异时性。 联体共生（年轻和年老动物的循环系统连接在一起）或年轻血浆 给药可以部分逆转与年龄相关的神经干/祖细胞（NPC）功能损伤， 异时性联体共生研究发现，老年大脑故意丧失认知能力。 全身环境影响的年龄依赖性双向性表明抗衰老因素 有人提出，年轻的血液会引起返老还童，而老年血液中的促衰老因素则会导致衰老。 减轻促衰老因素的影响也可能提供一种有效的延缓衰老的方法 表型，但最近我的实验室缺乏对个体促衰老因素的功能研究。 鉴定出 β2-微球蛋白 (B2M)，它是主要组织相容性复合物 1 类 (MHC I) 分子的组成部分， 作为一种系统性促衰老因子，对成人的再生和认知功能产生负面调节 拟议研究的目的是深入了解海马体的促衰老作用。 MHC I 分子对衰老大脑的影响，并确定针对老年大脑的这些分子的治疗潜力 具体来说，我们的假设是 B2M 与经典 MHC I 分子一起充当促衰老因子。 驱动成人海马体中与年龄相关的再生和认知障碍，我们将测试这一理论。 具有三个具体目标：1：表征 B2M 和 MHC I 下游的年龄相关分子机制 成人大脑潜在的再生和认知增强 2：确定减少的有效性。 细胞表面 MHC I 表达可改善与年龄相关的再生和认知障碍 3：研究。 经典 MHC I 分子 H2-Kd 和 H2-Db，作为再生和认知的促衰老负调节剂 成功完成这些研究将具有重大的转化潜力， 确定可作为改善痴呆相关新疗法的分子途径 神经退行性疾病及其在再生和再生受损方面的下游后果 认知功能。

项目成果

MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage.

MANF 调节衰老过程中的代谢和免疫稳态，并防止肝脏损伤。

• 发表时间: 2019
• 影响因子: 20.8
• 作者: Sousa;Neves, Joana;Cedron;Ventura, P Britten;Liao, Chen;Riley, Rebeccah R;Soifer, Ilya;van Bruggen, Nicholas;Kolumam, Ganesh A;Villeda, Saul A;Lamba, Deepak A;Jasper, Heinrich
• 通讯作者: Jasper, Heinrich

Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation.

与年龄相关的神经干细胞 O-GlcNAc 损失通过 STAT3 激活促进神经胶质细胞命运转换。

• 发表时间: 2020
• 影响因子: 11.1
• 作者: White 3rd, Charles W;Fan, Xuelai;Maynard, Jason C;Wheatley, Elizabeth G;Bieri, Gregor;Couthouis, Julien;Burlingame, Alma L;Villeda, Saul A
• 通讯作者: Villeda, Saul A

The aged hematopoietic system promotes hippocampal-dependent cognitive decline.

衰老的造血系统促进海马依赖性认知能力下降。

• 发表时间: 2020-08
• 影响因子: 7.8
• 作者: Smith, Lucas K;Verovskaya, Evgenia;Bieri, Gregor;Horowitz, Alana M;von Ungern;Lin, Karin;Seizer, Peter;Passegué, Emmanuelle;Villeda, Saul A
• 通讯作者: Villeda, Saul A

Tet 2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain

Tet 2 可挽救成年小鼠大脑中与年龄相关的再生衰退并增强认知功能

• 发表时间: 2024-09-14
• 作者: Géraldine Gontier;M. Iyer;Jeremy M. Shea;Gregor Bieri;Elizabeth G Wheatley;M. Ramalho;Saul A. Villeda
• 通讯作者: Saul A. Villeda

MICROGLIA AGING IN THE HIPPOCAMPUS ADVANCES THROUGH INTERMEDIATE STATES THAT DRIVE INFLAMMATORY ACTIVATION AND COGNITIVE DECLINE.

海马体中的小胶质细胞老化通过中间状态进展，从而驱动炎症激活和认知衰退。

• 发表时间: 2024-04-09
• 作者: Shea, Jeremy M;Villeda, Saul A
• 通讯作者: Villeda, Saul A