Project Grant R03HL182997

PROTEOMIC PROFILING AND NEUROCOGNITIVE ASSESSMENT TO UNCOVER STROKE MECHANISMS IN ADULTS WITH SICKLE CELL DISEASE - ABSTRACT STROKE IS A PREVALENT COMPLICATION AMONG THE OVER 120,000 AMERICANS WITH SICKLE CELL DISEASE (SCD), SIGNIFICANTLY CONTRIBUTING TO ANNUAL HEALTHCARE COSTS EXCEEDING $2.4 BILLION. STROKE, INCLUDING NEUROCOGNITIVE IMPAIRMENT, ASYMPTOMATIC CEREBRAL INFARCTION, AND ISCHEMIC OR HEMORRHAGIC STROKE, IS THE MOST FREQUENT NEUROLOGICAL SIDE EFFECT IN SCD. THE NERVOUS SYSTEM IS PARTICULARLY VULNERABLE TO DAMAGE FROM CHRONICALLY LOW HEMOGLOBIN (HGB) LEVELS AND REPEATED VASO-OCCLUSIVE CRISES (VOCS), LEADING TO ISCHEMIA-REPERFUSION OXIDATIVE STRESS AND INFLAMMATION. BY AGE 45, 24% OF PATIENTS WITH SCD EXPERIENCE A STROKE. DESPITE THIS, THE UNDERLYING MECHANISMS OF STROKE AND NEUROCOGNITIVE IMPAIRMENT IN SCD REMAIN UNDEREXPLORED. PRELIMINARY PROTEOMIC STUDIES ON PLATELETS FROM SCD PATIENTS REVEALED SIGNIFICANT INCREASES IN PROTEINS ASSOCIATED WITH NEURODEGENERATION, SUCH AS A-SYNUCLEIN (SNCA), AMYLOID BETA PRECURSOR PROTEIN (APP), AND TRANSCRIPTION FACTOR P65 (PINK1). THESE PROTEINS CONTRIBUTE TO NEURONAL DAMAGE AND THE PROGRESSIVE LOSS OF NERVE CELL FUNCTION. MITOCHONDRIAL DYSFUNCTION, PARTICULARLY REDUCED MITOPHAGY, IS LINKED TO INCREASED LEVELS OF MITOCHONDRIAL PROTEINS AND DECREASED LEVELS OF NEUROPROTECTIVE PROTEINS LIKE PARK7 (DJ-1). THESE PROTEOMIC ALTERATIONS HIGHLIGHT THE NEED FOR FURTHER INVESTIGATION INTO THE MECHANISMS DRIVING NEURODEGENERATION AND STROKE IN SCD PATIENTS. THIS STUDY AIMS TO IDENTIFY THE ENCODED ENDOPHENOTYPES AND EXAMINE PROTEIN INTERACTIONS RELATED TO NEUROCOGNITIVE OUTCOMES IN SCD. WE WILL SAMPLE 90 SEX- AND AGE-MATCHED ADULTS: 30 HEALTHY CONTROLS, 30 INDIVIDUALS WITH SCD AND NO HISTORY OF STROKE, AND 30 INDIVIDUALS WITH SCD AND A HISTORY OF STROKE. AIM 1 WILL QUANTIFY NEURODEGENERATION-ASSOCIATED AND MITOCHONDRIAL PROTEINS IN THESE GROUPS. AIM 2 WILL EXAMINE ASSOCIATIONS BETWEEN HGB LEVELS, NEURODEGENERATION, AND COGNITIVE FUNCTION USING NEUROCOGNITIVE QUESTIONNAIRES AND NEUROQOL. THE IMPACT OF THIS STUDY WILL EXTEND FINDINGS FROM PREVIOUS RESEARCH AND HELP IDENTIFY SPECIFIC PROTEIN BIOMARKERS ASSOCIATED WITH NEURODEGENERATION AND STROKE IN SCD PATIENTS. THIS COULD LEAD TO BETTER DIAGNOSTIC TOOLS AND TARGETED THERAPIES, ULTIMATELY IMPROVING PATIENT OUTCOMES AND REDUCING THE HEALTHCARE BURDEN ASSOCIATED WITH THIS SEVERE COMPLICATION.