RF1AG064227

O-GLCNAC HOMEOSTASIS REGULATES MITOCHONDRIAL FUNCTION IN ALZHEIMER'S DISEASE - PROJECT SUMMARY: CURRENTLY, 6.9 MILLION AMERICANS ARE SUFFERING FROM ALZHEIMER'S DISEASE (AD), WHICH IS THE ONLY MAJOR DISEASE LACKING GOOD PREVENTION METHODS, TREATMENTS, OR A CURE. OUR OBJECTIVE IS TO DETERMINE THE MECHANISMS AS TO HOW NUTRIENT SENSING AS INTERPRETED BY O-GLCNACYLATION, A DYNAMIC SINGLE SUGAR MODIFICATION, INFLUENCES MITOCHONDRIAL FUNCTION IN ALZHEIMER'S DISEASE (AD). O-GLCNAC IS CATEGORIZED BY THE ADDITION OF A SINGLE O- LINKED Β-N-ACETYL-D-GLUCOSAMINE MOIETY TO SERINE/THREONINE AMINO ACIDS OF NUCLEAR AND CYTOPLASMIC PROTEINS. THIS MODIFICATION IS RESPONSIVE TO EXTRACELLULAR SIGNALS SUCH HORMONES, NUTRIENTS, AND ENVIRONMENTAL CUES AND IS INVOLVED IN REGULATING NUMEROUS CELLULAR FUNCTIONS SUCH AS THE CELL CYCLE, STRESS RESPONSE, TRANSCRIPTION, AND TRANSLATION. THE ENZYMES RESPONSIBLE FOR PROCESSING THE MODIFICATION ARE O-GLCNAC TRANSFERASE (OGT), WHICH ADDS THE MODIFICATION, AND O-GLCNACASE (OGA), WHICH REMOVES THE MODIFICATION. IMPORTANTLY, CHANGES IN O- GLCNACYLATION ALTER MITOCHONDRIAL FUNCTION. CELLS ACTIVELY MAINTAIN HOMEOSTATIC LEVELS IN O-GLCNAC, AND CELLS WILL ALTER THE EXPRESSION OF OGT AND OGA TO MODULATE O-GLCNACYLATION DUE TO CHANGES IN THE ENVIRONMENT. WE HYPOTHESIZE THAT THE LOSS OF O-GLCNAC HOMEOSTASIS CAUSES MITOCHONDRIAL DYSFUNCTION PROMOTING THE ONSET AND PROGRESSION OF AD. SUPPORTING THIS HYPOTHESIS, WE RECENTLY DEMONSTRATED THAT O-GLCNAC REGULATES MITOCHONDRIAL RESPIRATION, MITOPHAGY, AND MITOCHONDRIAL RETROGRADE SIGNALING; THUS, WE GENERATED TWO SPECIFIC AIMS TO TEST THIS HYPOTHESIS, AND WE HAVE DEVELOPED SEVERAL O-GLCNAC RELATED TOOLS TO ACCOMPLISH OUR GOALS. IN AIM 1, WE WILL ELUCIDATE O-GLCNAC MECHANISTIC CONTROL OF MITOCHONDRIAL FUNCTION BY IDENTIFYING THE OGT AND OGA MITOCHONDRIAL INTERACTOME IN CONTROL AND AD MITOCHONDRIA AND TEST HOW THESE INTERACTIONS IMPACT MITOCHONDRIAL FUNCTION; IDENTIFY ELECTRON TRANSPORT PROTEINS THAT PREFER TO INTERACT WITH O-GLCNACYLATED PROTEINS AND HOW THESE INTERACTIONS AFFECT ENERGETICS; ELUCIDATE THE FUNCTION OF O-GLCNAC ON PINK1 (PTEN INDUCED KINASE 1), WHICH IS KEY REGULATOR OF MITOPHAGY, AND LASTLY EXPLORE SEX-SPECIFIC EFFECTS OF OGA INHIBITION (A POTENTIAL AD THERAPEUTIC) ON MITOCHONDRIAL FUNCTION. THESE DATA WILL PROVIDE NOVEL MECHANISTIC INFORMATION ON HOW O-GLCNAC AND THE FUNCTIONS OF OGT AND OGA CONTRIBUTE TO MITOCHONDRIAL FUNCTION AND AD DEVELOPMENT. IN OUR SECOND AIM, WE WILL ASCERTAIN HOW ALTERED O-GLCNAC NUTRIENT SENSING AFFECTS MITOCHONDRIAL RETROGRADE SIGNALING TO THE NUCLEUS. WE IDENTIFIED THAT THE FUNCTION OF RETROGRADE SIGNALING TRANSCRIPTION FACTORS ATF4 (ACTIVATING TRANSCRIPTION FACTOR 4) AND NRF2 (NUCLEAR FACTOR ERYTHROID 2) ARE MODULATED BY O-GLCNAC. WE WILL EMPLOY A NOVEL CRISPR BASED TARGETING OF OGT AND OGA TO ATF4 AND NRF2 TARGET GENE PROMOTERS TO DETERMINE HOW O-GLCNACYLATION ORGANIZES CIS-REGULATORY ELEMENTS AT THESE PROMOTERS. NEXT, WE WILL IDENTIFY HOW O-GLCNAC ON NRF2 AFFECTS NRF2 FUNCTION. TOGETHER, THESE DATA WILL DEMONSTRATE THE ROLE OF O-GLCNAC HOMEOSTASIS IN REGULATING NUCLEAR MITOCHONDRIAL GENE EXPRESSION THROUGH MITOCHONDRIA RETROGRADE SIGNALING. COLLECTIVELY, THESE RESULTS WILL PROVIDE NEW MECHANISTIC PATHWAYS IN OUR UNDERSTANDING OF AD.

University Of Kansas Medical Center Research Institute

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]

Kansas City, Kansas 66160 United States

Single Zip Code

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