RF1AG093995

A BENEFICIAL PERSISTENT DNA DAMAGE-INDUCED IMMUNE RESPONSE IN AGING - PRIJECT SUMMARY/ABSTRACT THE SYSTEMIC IMMUNE EFFECTS OF DNA DAMAGE IN AGING AND DISEASE REMAIN ELUSIVE. IT IS GENERALLY BELIEVED THAT IMMUNE RESPONSES TRIGGERED BY TRANSIENT DNA DAMAGE ARE BENEFICIAL WHILE THOSE ASSOCIATED WITH PERSISTENT DNA DAMAGE ARE DETRIMENTAL. WE RECENTLY REPORTED THAT NLRP12 (NOD-LIKE RECEPTOR 12), A MEMBER OF THE NLR INFLAMMASOME FAMILY THAT PLAYS A CENTRAL ROLE IN INNATE IMMUNITY, IS INDUCED BY PERSISTENT DNA DAMAGE, AND THAT PERSISTENT DNA DAMAGE-INDUCED NLRP12 IMPROVES THE FUNCTION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS) IN BOTH MOUSE AND HUMAN MODELS OF DNA REPAIR DEFICIENCY AND AGING. THESE RESULTS ARGUE A PROTECTIVE ROLE OF NLRP12 IN THE CONTEXT OF IMMUNE RESPONSE TO PERSISTENT DNA DAMAGE UNDER CONDITIONS OF DNA REPAIR DEFICIENCY AND AGING. HOWEVER, THE MECHANISM UNDERPINNING THE LINK BETWEEN PERSISTENT DNA DAMAGE AND NLRP12 EXPRESSION IN DISEASE AND AGING HAS NOT BEEN DEFINED. TO EXPLOIT THIS, WE PERFORMED PRELIMINARY MECHANISTIC STUDIES AND FOUND THAT PERSISTENT DNA DAMAGE INDUCED ABUNDANT CYTOSOLIC DSDNA AND CONSEQUENTLY ACTIVATION OF THE CYCLIC GMP-AMP SYNTHASE (CGAS)-STIMULATOR OF INTERFERON GENES (STING) PATHWAY IN HSPCS FROM DNA REPAIR-DEFICIENT (FANCA-/-) AND AGED MICE TREATED WITH IONIZING RADIATION (IR) OR THE DNA CROSS-LINKER MITOMYCIN C (MMC). CONCOMITANTLY, A MAJOR TRANSCRIPTION FACTOR FOR NLRP12, PU.1, WAS ALSO ELEVATED. WE FURTHER SHOWED THAT INHIBITION OF THE CGAS-STING PATHWAY PU.1 ABOLISHED PERSISTENT DNA DAMAGE-INDUCED NLRP12 EXPRESSION IN THESE DAMAGED HSPCS, SUGGESTING A POTENTIAL LINK BETWEEN THE CGAS-STING PATHWAY AND PERSISTENT DNA DAMAGE-INDUCED NLRP12 EXPRESSION. TO FURTHER INVESTIGATE THIS NOVEL MECHANISTIC LINK AND ITS FUNCTIONAL IMPLICATIONS, WE GENERATED A CONDITIONAL NLRP12 MOUSE MODEL, WITH WHICH WE DELETED THE NLRP12 GENE SPECIFICALLY IN THE HEMATOPOIETIC LINEAGES USING THE VAV1-CRE DELETER STRAIN. WE OBSERVED EXACERBATED AGING PHENOTYPES IN NLRP12-DEFICIENT FANCA-/- AND AGED MICE, ACCOMPANIED WITH THE SENESCENCE ASSOCIATED SECRETORY PHENOTYPE (SASP) IN THE BONE MARROW (BM) AND A SIGNIFICANT INCREASE IN PYROPTOSIS IN BM HSPCS. FURTHERMORE, DELETION OF NLRP12 SIGNIFICANTLY INCREASED CYTOPLASMIC LOCALIZATION OF NLRP3, A HALLMARK OF NLRP3 INFLAMMASOME ACTIVATION IN THE NLRP12-DEFICIENT FANCA-/- AND AGED HSPCS. THESE PRELIMINARY STUDIES SUGGEST A NOVEL INTERPLAY BETWEEN PERSISTENT DNA DAMAGE AND IMMUNE RESPONSE: CGAS-STING-MEDIATED UPREGULATION OF NLRP12 AS A SYSTEMIC PRO-HOMEOSTATIC EFFECTOR OF IMMUNE RESPONSE TO OTHERWISE DETRIMENTAL PERSISTENT DNA DAMAGE. WE HYPOTHESIZE THAT PERSISTENT DNA DAMAGE ACTIVATES A NON-CANONICAL CGAS-STING-PU.1 PATHWAY TO INDUCE THE UPREGULATION OF NLRP12, WHICH SUPPRESSES SASP TO IMPEDE CHRONIC INFLAMMATION AND INHIBITS NLRP3 INFLAMMASOME TO PREVENT HSPC PYROPTOSIS. THE GOALS OF THE PROJECT ARE TO INVESTIGATE: (1) THE MECHANISMS LINKING PERSISTENT DNA DAMAGE TO NLRP12 UPREGULATION AND (2) THE FUNCTIONAL LINKS BETWEEN PERSISTENT DNA DAMAGE AND UPREGULATED NLRP12 IN AGING HEMATOPOIESIS.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

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]

Pennsylvania United States

State-Wide

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