RF1AG068168

EXTRACELLULAR VESICLE TREATMENT AND AGE-RELATED NEUROPATHOLOGY IN NON-HUMAN PRIMATES - ABSTRACT IN OUR PREVIOUS GRANT (R01AG068168) WE DEMONSTRATED THE EFFICACY OF MESENCHYMAL STROMAL CELL (MSC)-DERIVED EXTRACELLULAR VESICLES (EVS) FROM YOUNG MONKEYS TO SLOW OR REVERSE AGE-RELATED COGNITIVE DECLINE IN AGING RHESUS MONKEYS. COMPARED TO CONTROLS, EV-TREATED MONKEYS SHOWED A HIGHER LEVEL OF PERFORMANCE ON A SPATIAL WORKING MEMORY TASK, WHICH WAS CORRELATED WITH INCREASED AΒ42 PROTEIN CONCENTRATION IN THE CSF, POSSIBLY DUE TO ENHANCED CLEARANCE. EV-MEDIATED IMPROVED SPATIAL WORKING MEMORY WAS ALSO CORRELATED WITH ENHANCED WHITE MATTER INTEGRITY, FUNCTIONAL CONNECTIVITY IN VIVO AND GREATER EXCITABILITY OF PYRAMIDAL NEURONS IN PREFRONTAL CORTEX, POINTING TO COMPENSATORY MECHANISMS THAT MAY PROMOTE PLASTICITY DURING AGING. IN ADDITION, EXTENSIVE PROTEOMIC PROFILING OF THE CONTENTS OF OUR MONKEY EVS IDENTIFIED THE ENRICHMENT OF PROTEINS INVOLVED IN SEVERAL NEURITOGENIC AND SYNAPTOGENIC PROCESSES THAT PROVIDE MECHANISTIC INSIGHT ON THE ABILITY OF THE EVS TO AMELIORATE AGE-RELATED CHANGES IN THE BRAIN. FURTHERMORE, OUR IN VITRO STUDIES SHOWED THAT EVS MITIGATE AGE- AND AD-RELATED NEURODEGENERATIVE CHANGES IN HUMAN-DERIVED CORTICAL ORGANOIDS (COS). TOGETHER THESE FINDINGS DEMONSTRATE THE SIGNIFICANT THERAPEUTIC EFFICACY OF MSC-EVS IN AGING. HOWEVER, RECENT EVIDENCE HAS DEMONSTRATED SEX DIFFERENCES IN THE CARGO AND GENE EXPRESSION IN EVS. RECENT TRANSCRIPTOMIC STUDIES HAVE DEMONSTRATED THAT EVS FROM MALE DONORS EXPRESS A GREATER VARIETY AND ABUNDANCE OF RNAS THAN THOSE FROM FEMALE DONORS.6 FURTHER, DIFFERENTIALLY EXPRESSED GENES (DEG) IN MALE EVS WERE ASSOCIATED WITH INTRACELLULAR SIGNALING AND VESICLE TRANSPORT, WHEREAS DEGS IN FEMALE EVS WERE ASSOCIATED WITH EXTRACELLULAR MATRIX ORGANIZATION AND SIGNAL TRANSMISSION. THESE OUTCOMES SUGGEST THAT MALE AND FEMALE EVS MAY SUPPORT DIFFERENT BIOLOGICAL, REPAIR AND IMMUNOMODULATORY PROCESSES AND THEREFORE MAY HAVE DIFFERENT EFFECTS ON THE AGED BRAIN.6 IN THE PREVIOUS GRANT, OUR STUDIES USED EVS FROM BOTH MALE AND FEMALE DONORS. HOWEVER, OUR MOST RECENT DATA SHOWED A POSITIVE EFFECT OF FEMALE EVS ON COGNITION, WHITE MATTER INTEGRITY AND NEUROPATHOLOGICAL DEBRIS CLEARANCE. IN THIS RENEWAL, WE NOW PROPOSE TO CONDUCT AN IN-DEPTH ANALYSIS OF THE MECHANISTIC ACTION AND EFFICACY OF EVS FROM MSCS FROM BOTH MALE AND FEMALE DONORS, TO DETERMINE SEX DIFFERENCES IN THE ABILITY OF EVS TO AMELIORATE AGE-RELATED IMPAIRMENTS IN COGNITION, FACILITATE CLEARANCE OF NEURODEGENERATIVE DEBRIS AND REDUCE INFLAMMATION IN MONKEYS AND HUMAN-DERIVED COS. BASED ON OUR DATA AND EVIDENCE FROM THE LITERATURE WE HYPOTHESIZE THAT EVS DERIVED FROM FEMALE MSCS WILL HAVE MORE EFFICACIOUS THERAPEUTIC BENEFITS, INCLUDING INCREASED CLEARANCE OF AGE-RELATED NEURODEGENERATIVE DEBRIS THAT WILL CORRELATE WITH WHITE MATTER INTEGRITY, NEURONAL PLASTICITY AND IMPROVED COGNITIVE FUNCTION.

Trustees Of Boston University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Massachusetts United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)