Project Grant R15NS111413

THE ROLE OF THE P75 NEUROTROPHIN RECEPTOR IN DOPAMINERGIC NEURODEGENERATION INDUCED BY OXIDATIVE STRESS. - NEURODEGENERATIVE DISEASES, WHICH ARE CHARACTERIZED BY PROGRESSIVE NEURAL DYSFUNCTION AND NEURONAL DEATH, ARE A COMMON CAUSE OF MORBIDITY AND MORTALITY IN THE ELDERLY. BECAUSE CURRENT TREATMENT STRATEGIES FOR MOST NEURODEGENERATIVE DISORDERS ARE PALLIATIVE RATHER THAN CURATIVE, THERE IS AN URGENT NEED FOR NOVEL TREATMENT STRATEGIES THAT REDUCE OR PREVENT PROGRESSIVE NEURODEGENERATION. THE P75 NEUROTROPHIN RECEPTOR (P75NTR) IS A TRANSMEMBRANE PROTEIN THAT HAS BEEN DEMONSTRATED TO REGULATE THE DEATH OF NEURONS AFFECTED BY A VARIETY OF PATHOLOGICAL CONDITIONS. DESPITE THIS KNOWN ROLE, HOW THE RECEPTOR IS ACTIVATED IN DAMAGED NEURONS AND THE MECHANISMS THROUGH WHICH IT REGULATES CELL DEATH ARE POORLY UNDERSTOOD. USING CULTURED DOPAMINERGIC CELLS, WE RECENTLY DISCOVERED A NOVEL, LIGAND-INDEPENDENT MECHANISM THROUGH WHICH P75NTR IS ACTIVATED IN RESPONSE TO OXIDATIVE STRESS. HOWEVER, THE SIGNALING EVENTS ASSOCIATED WITH THIS NEW RECEPTOR ACTIVATION MECHANISM AND THE PHYSIOLOGICAL CONSEQUENCES OF SUCH EVENTS REMAIN INCOMPLETELY UNDERSTOOD. INVESTIGATIONS IN THIS REGARD MAY BE PARTICULARLY IMPORTANT TO UNDERSTANDING THE PROGRESSION OF PARKINSON'S DISEASE, A DISORDER ASSOCIATED WITH OXIDATIVE STRESS AND PROGRESSIVE DEGENERATION OF DOPAMINERGIC NEURONS IN THE SUBSTANTIA NIGRA OF THE VENTRAL MIDBRAIN. WITH THESE CONSIDERATIONS, WE PROPOSE TO EVALUATE THE EFFECTS OF P75NTR ON DOPAMINERGIC NEURODEGENERATION IN CELL CULTURE AND ANIMAL MODELS OF PARKINSON'S DISEASE. AIM I OF THIS APPLICATION IS TO CHARACTERIZE THE MECHANISMS THROUGH WHICH OXIDATIVE STRESS INDUCES P75NTR SIGNALING. BIOCHEMICAL ASSAYS WILL BE PERFORMED USING LYSATES OF CULTURED CELLS TO IDENTIFY THE ROLES OF VARIOUS P75NTR INTERACTORS IN OXIDATIVE STRESS-INDUCED P75NTR SIGNALING. AIM II OF THE PROPOSED WORK IS TO USE BLOCKADE OF P75NTR SIGNALING BY SIRNA-MEDIATED KNOCKDOWN, GENETIC DELETION, OR PHARMACOLOGICAL INHIBITION TO EVALUATE THE EFFECTS OF THE RECEPTOR ON DOPAMINERGIC NEURODEGENERATION IN CELL CULTURE OR MOUSE MODELS OF PARKINSON'S DISEASE. SINCE AXONAL DEGENERATION IN DOPAMINERGIC NEURONS IS A KEY, EARLY-STAGE EVENT THAT PRECEDES NEURONAL DEATH IN INDIVIDUALS WITH PARKINSON'S DISEASE, AIM III OF THE PROPOSED RESEARCH PROJECT IS TO EVALUATE THE EFFECTS OF P75NTR SIGNALING ON AXONAL DEGENERATION INDUCED BY OXIDATIVE STRESS. ALL STUDIES IN THIS PROPOSAL WILL INVOLVE UNDERGRADUATE STUDENTS AT EASTERN KENTUCKY UNIVERSITY (EKU). THESE STUDENTS WILL ALSO PARTICIPATE IN WEEKLY LAB MEETINGS AND RECEIVE PERSONAL MENTORSHIP IN SCIENCE LITERACY, EXPERIMENTAL DESIGN, RESEARCH METHODOLOGY, DATA ANALYSIS, AND COMMUNICATION OF FINDINGS. BY SUPPORTING THIS MERITORIOUS RESEARCH, AN AREA GRANT WOULD PROVIDE IMPACTFUL RESEARCH EXPERIENCES FOR STUDENTS AND STRENGTHEN THE SCIENTIFIC ENVIRONMENT AT EKU, AN INSTITUTION WITH ACCELERATING EMPHASIS ON BIOMEDICAL RESEARCH.