RF1NS142703

A FULLY HUMANIZED FUNCTIONAL GENOMIC SCREEN TO IDENTIFY AND VALIDATE PAIN THERAPEUTIC TARGETS - ABSTRACT: THIS PROJECT WILL LEVERAGE A HIGHLY INNOVATIVE AND UNIQUE CRISPR-BASED SCREENING PLATFORM BUILT AND VALIDATED BY THE NEELY LAB AT UNIVERSITY OF SYDNEY IN AUSTRALIA AND AN UNPARALLELED HUMAN DORSAL ROOT GANGLION (DRG) TRANSCRIPTOMIC DATASET INCLUDING EXTENSIVE DATA FROM NEUROPATHIC PAIN PATIENTS AND AN ENTIRELY HUMAN- BASED IN VITRO VALIDATION PLATFORM CREATED BY THE PRICE LAB AT UNIVERSITY OF TEXAS AT DALLAS. THE OVERARCHING GOAL OF THE PROJECT WILL BE TO IDENTIFY AND VALIDATE HIGH QUALITY TARGETS FOR CHRONIC PAIN TREATMENT STARTING WITH HUMAN DISEASE-BASED DATA, FOLLOWED BY SCREENING AGAINST RECEPTORS FOUND IN HUMAN DRG, AND CULMINATING IN FUNCTIONAL VALIDATION USING HUMAN DRG NEURONS. TWO PATHS TO TARGET IDENTIFICATION AND VALIDATION WILL BE TAKEN. THE 1ST AIM WILL BE BASED ON THE FUNCTIONAL REGULATION OF ION CHANNELS OR RECEPTORS THAT ARE AT THE CORE OF HUMAN NOCICEPTOR FUNCTION. NAV1.7, TRPV1 AND THE TYPE 1 CYTOKINE SIGNAL TRANSDUCER GP130 ARE REQUIRED FOR NORMAL NOCICEPTOR FUNCTION AND CLEARLY LINKED TO CHRONIC PAIN, BUT MECHANISMS THROUGH WHICH THEY ARE REGULATED IN HUMAN NOCICEPTORS ARE NOT KNOWN. WE WILL GENERATE HUMAN CELL LINES EXPRESSING CORE PAIN RECEPTORS AND WE WILL KNOCKOUT OR TURN ON EVERY HUMAN GENE EVALUATING RESPONSES TO STIMULATION OF THESE CELLS. FROM THESE SCREENS WE WILL GENERATE KNOCKOUT OR UPREGULATED LINES TO CONFIRM FUNCTIONAL IMPACT OF EACH TARGET. WE WILL THEN VALIDATE USING HUMAN DRG NEURONS USING CRISPR-BASED GENE MANIPULATION. THE WORK IN THE FIRST AIM WILL LEAD TO A NEW UNDERSTANDING OF REGULATION OF CRITICAL ION CHANNELS AND RECEPTORS FOR PAIN THAT IS NOT POSSIBLE IN A CANDIDATE- BASED ANIMAL MODEL TESTING PARADIGM TRADITIONALLY USED IN THE FIELD. WE ANTICIPATE THAT THIS WORK, WHICH IS SUPPORTED BY AMPLE PRELIMINARY DATA FROM BOTH LABORATORIES, WILL SET A NEW STANDARD FOR TARGET IDENTIFICATION AND VALIDATION IN PAIN. AIM 2 WILL CAPITALIZE ON EXTENSIVE DATASETS IDENTIFYING FACTORS ASSOCIATED WITH NEUROPATHIC PAIN IN MALE AND FEMALE NEUROPATHIC PAIN PATIENTS. CRLF1 IS THE SOLE GENE THAT IS UPREGULATED IN BOTH MALE AND FEMALE THORACIC VERTEBRECTOMY NEUROPATHIC PAIN PATIENTS. WE WILL USE THE GENOME-WIDE CRISPR SCREEN TO IDENTIFY HOW THIS AND SIMILAR FACTORS ACT VIA RECEPTORS EXPRESSED IN THE HUMAN GENOME. WE WILL USE THIS INFORMATION TO VALIDATE THE TARGET RECEPTORS ON HUMAN DRG NEURONS FROM ORGAN DONORS AND THEN PERFORM FURTHER FUNCTIONAL CHARACTERIZATION TO UNDERSTAND SIGNALING MECHANISMS. IN BOTH AIMS WE WILL USE EXTENSIVE SEQUENCING DATASETS TO EVALUATE AND PRIORITIZE VALIDATED TARGETS BASED ON POTENTIAL SIDE-EFFECT PROFILES AND ADDICTION LIABILITIES. THE PROJECT BRINGS TOGETHER TWO LABS WITH UNIQUE RESOURCES AND EXPERTISE TO USE CUTTING EDGE TECHNOLOGIES TO IDENTIFY AND VALIDATE NEW TARGETS FOR PAIN TREATMENT BASED ENTIRELY ON HUMAN FUNCTIONAL GENOMICS, MOLECULAR NEUROSCIENCE, NEURO-IMMUNOLOGY AND PHARMACOLOGY.

University Of Texas At Dallas

(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.

93.279 - Drug Abuse and Addiction Research Programs

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Texas United States

State-Wide

HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed) (RFA-NS-22-034)