RF1NS143014

FUNCTIONAL AND MULTI-OMICS APPROACHES TO ELUCIDATE THE REGULATION OF PROTEASOME COMPLEX IN NEURODEGENERATIVE DISEASES - A HALLMARK FEATURE OF NEURODEGENERATIVE DISEASES (NDS) IS THE ACCUMULATION AND AGGREGATION OF DISEASE-SPECIFIC PROTEINS IN DISTINCT BRAIN REGIONS, LEADING TO CELLULAR DYSFUNCTION, LOSS OF SYNAPTIC CONNECTIONS, AND DEGENERATION. OFTEN IGNORED NONETHELESS, A MAJOR COMPONENT OF ALL AGGREGATES IS UBIQUITIN, IMPLICATING THAT DYSREGULATED UBIQUITIN-PROTEASOME MEDIATED DEGRADATION IS EITHER A CONSEQUENCE OF THE DISEASE PATHOGENESIS OR THAT MALADAPTIVE PROTEASOMAL DEGRADATION IS ONE OF THE COMMON DRIVERS OF NDS. IN ALZHEIMER'S DISEASE (AD), NEUROFIBLIRALY TANGLES (NFT) AND NEURITIC PLAQUES (NP) ARE DECORATED WITH UBIQUITIN, AND A WILDLY HELD BELIEF BUT NOT RIGOROUSLY TESTED IS THAT TAU AGGREGATES IMPEDE PROTEOLYSIS, CAUSING A BUILD-UP OF UBIQUITINATED INCLUSION. HISTORICALLY, THIS HYPOTHESIS HAS PLACED THE PROTEASOME-MEDIATED PROTEOLYSIS DYSFUNCTION IN AD DISTAL TO THE DISEASE PATHOGENESIS. AS A RESULT, THE FIELD HAS SHOWN LITTLE INTEREST IN THE POTENTIAL ROLE OF THE PROTEASOME IN DETERMINING THE OVERALL OUTPUT OF THE UBIQUITIN-PROTEASOME SYSTEM (UPS) IN ALZHEIMER’S AND OTHER NDS. HOWEVER, RECENT STUDIES IN THE FIELD RECOGNIZE PROTEASOME AS A FUNDAMENTAL COMPONENT OF THE REGULATION OF THE UPS AND PROTEIN HOMEOSTASIS AND THAT PROTEASOME’S (DYS)REGULATED LEVELS AND ACTIVITY COULD PREDICT THE OUTCOME OF PROTEIN BUILD-UP IN AD AND OTHER NDS. WHILE FUNCTIONAL CHANGES IN THE PROTEASOME MACHINERY MAY CONSTITUTE A COMMON CONTRIBUTING FACTOR TO THE PATHOGENESIS OF NDS, THIS CO-OCCURRING PATHOLOGY ACROSS DISEASES, IN THE PAST, HAS BEEN STUDIED IN ISOLATION FROM ONE ANOTHER. USING INTEGRATED MULTI-OMICS APPROACHES COMBINED WITH BIOCHEMICAL AND FUNCTIONAL APPROACHES PROPOSED IN AIM 1 AND 2, THIS APPLICATION WILL INVESTIGATE HOW THE UPS, SPECIFICALLY THE PROTEASOME COMPLEXES, ARE AFFECTED IN AD (IN EARLY AND LATE STAGES), PROGRESSIVE SUPRANUCLEAR PALSY (PSP), PARKINSON’S, AND AMYLOID LATERAL SCLEROSIS (ALS) AND ELUCIDATE A POSSIBLE SHARED MECHANISTIC CASCADE OF THE FAILED PROTEIN BREAKDOWN BY THE 26S PROTEASOME ACROSS CLINICALLY DIVERSE NDS. FOCUSING PRIMARILY ON AD PATHOGENESIS AS A REPRESENTATIVE DISEASE, AIM 3 WILL INTERROGATE THE NEGATIVE AND POSITIVE REGULATION OF THE NFE2L/NRF1, A MASTER TRANSCRIPT FACTOR OF THE PROTEASOME GENES, TO UNCOVER THE ROLE OF NRF1-MEDIATED PROTEOLYSIS IN AD-AFFLICTED BRAINS, AND PROPOSE A TRANSLATIONAL APPROACH OF PROTEASOME-TARGETING INTERVENTION THAT COULD OVERCOME PROTEASOME IMPAIRMENT AND PROTEIN AGGREGATION IN AD.

The Trustees Of Columbia University In The City Of New York

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (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. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND 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 of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

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

New York United States

State-Wide

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-22-093)