RF1NS142171

CHARACTERIZATION OF ANTIGEN-SPECIFIC IMMUNE RESPONSE IN ALS - PROJECT SUMMARY AMYOTROPHIC LATERAL SCLEROSIS (ALS) IS A FATAL NEURODEGENERATIVE DISEASE THAT PRIMARILY AFFECTS MOTOR NEURONS (MNS) IN THE BRAIN AND SPINAL CORD. THE RESULTING CLINICAL PRESENTATION IS HETEROGENEOUS AND EXISTS ON A SPECTRUM RANGING FROM PURE MOTOR INVOLVEMENT (ALS) TO PURE COGNITIVE INVOLVEMENT (FRONTOTEMPORAL DEMENTIA; FTD) REFERRED TO AS THE ALS/FTD SPECTRUM. OVER THE PAST DECADE, INCREASING LINES OF EVIDENCE HAVE REVEALED A POTENTIAL ROLE FOR IMMUNITY IN ALS PATHOPHYSIOLOGY; HOWEVER, THIS ASSOCIATION IN THE HUMAN SYSTEM REMAINS NOT WELL DESCRIBED. MISLOCALIZATION OF TAR DNA-BINDING PROTEIN OF 43KDA (TDP-43) IN 97% OF ALS CASES, IS A HALLMARK OF ALS/FTD AND LEADS TO THE GENERATION OF DE NOVO PEPTIDES/PROTEINS IN THE CENTRAL NERVOUS SYSTEM (CNS). WE POSIT THAT THESE DE NOVO PROTEINS, IN ADDITION TO POST-TRANSLATIONALLY MODIFIED ALS-SPECIFIC AGGREGATES, MAY BE IMMUNOGENIC AND CONTRIBUTE TO UNDERLYING DISEASE PATHOPHYSIOLOGY. FURTHERMORE, ABERRANT CLONAL T CELL RESPONSES HAVE BEEN IMPLICATED IN ALS PATHOGENESIS, AND ALS MICROGLIA ARE PRO-INFLAMMATORY AND HAVE TOXIC EFFECTS ON MNS. HERE, WE WILL LEVERAGE AN UNBIASED APPROACH TO IDENTIFY SELF- AND NON-SELF PEPTIDES/ANTIGENS PRESENTED TO BRAIN-INFILTRATED T CELL RESPONSES IN ALS/FTD. OUR OVERALL GOAL IS TO DECODE THE IMMUNE LANDSCAPE IN THE BRAIN OF SPORADIC AND FAMILIAL ALS PATIENTS AND CONTROL SUBJECTS THROUGH THE IDENTIFICATION OF THE IMMUNOGENIC PROTEINS PRESENTED BY MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS I MOLECULE EXPRESSED ON MICROGLIA, MAPPING OF THEIR RECOGNITION BY COGNATE T CELL RECEPTORS (TCRS) IN ALS/FTD. WHILE PRIOR EFFORTS IN OTHER DISEASES (E.G., TYPE 1 DIABETES) HAVE SPANNED DECADES TO LINK ANTIGENS TO TCRS, THIS PROPOSED STUDIES IN ALS/FTD WILL BE CATALYZED BY THE MULTI-DISCIPLINARY EXPERTISE OF OUR INTERDISCIPLINARY TEAM. WE HAVE ACCESS TO POSTMORTEM TISSUE FROM ALS PATIENTS AND CONTROL SUBJECTS (N=30) AS WELL AS BLOOD CELLS FROM LIVING ALS PATIENTS AND HEALTHY CONTROLS (N=40). WE WILL USE THESE SPECIMENS TO IDENTIFY MHC-BOUND PEPTIDES/ANTIGENS IN THE ALS/FTD BRAIN TO CHARACTERIZE THE PHENOTYPE AND CLONALITY OF BRAIN-RECRUITED T CELLS IN THE BLOOD OF ALS PATIENTS. TO DECODE THE IMMUNE LANDSCAPE IN ALS, WE WILL ADDRESS THE FOLLOWING QUESTIONS: (I) WHICH ANTIGENS ARE PRIMING T CELLS IN THE ALS/FTD BRAIN, (II) WHAT ARE THE ALS-RELEVANT ANTIGEN-TCR PAIRS, (III) WHAT IS THE PHENOTYPE OF CLONALLY-EXPANDED T CELLS, AND (IV) HOW CAN THESE ALS/FTD-SPECIFIC ANTIGEN-TCR PAIRS INFORM OUR UNDERSTANDING OF THE DISEASE PATHOGENESIS AND PROGRESSION. LEVERAGING THE IMMUNE SYSTEM TO HALT AND/OR REDUCE THE PROGRESSION OF ALS/FTD HOLDS GREAT PROMISE. OUR LACK OF PRECISION IN KNOWING WHICH ANTIGENS AND WHICH TCRS ARE RELEVANT FOR ALS/FTD IS A KEY BARRIER TO ADVANCING PRECISION IMMUNOTHERAPIES, ALONGSIDE THOSE TARGETING CELL-AUTONOMOUS MECHANISMS OF NEURODEGENERATION.

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, New York 100323725 United States

Single Zip Code

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