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.

项目总结/文摘

项目成果

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。

• DOI: 10.1101/2024.04.09.588665
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Shea,JeremyM;Villeda,SaulA
• 通讯作者: Villeda,SaulA

Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain.

• DOI: 10.1016/j.celrep.2018.02.001
• 发表时间: 2018-02-20
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Gontier G;Iyer M;Shea JM;Bieri G;Wheatley EG;Ramalho-Santos M;Villeda SA
• 通讯作者: Villeda SA

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。

• DOI: 10.1111/acel.13192
• 发表时间: 2020
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Smith,LucasK;Verovskaya,Evgenia;Bieri,Gregor;Horowitz,AlanaM;vonUngern-Sternberg,SaskiaNI;Lin,Karin;Seizer,Peter;Passegué,Emmanuelle;Villeda,SaulA
• 通讯作者: Villeda,SaulA