Project Grant R43HL166091

ADDRESSING THE CONTINUING CHALLENGE OF IDENTIFYING AND MANAGING CORONARY RISK: A PERSON-SPECIFIC STRATEGY USING PROTEOMICS - PROJECT SUMMARY/ABSTRACT: DESPITE CONSIDERABLE ADVANCES IN THE PREVENTION AND MANAGEMENT OF CORONARY DISEASE (CAD), SEVERAL HUNDRED THOUSAND AMERICANS EXPERIENCE MYOCARDIAL INFARCTIONS EACH YEAR. ONE REASON IS THAT CURRENT CLINICAL RISK ASSESSMENT DOES NOT ENCOMPASS MANY RESIDUAL RISK FACTORS, E.G. OXIDATIVE STRESS. ENDOTHELIAL-DEPENDENT CORONARY VASCULAR DYSFUNCTION IS A "FINAL COMMON PATHWAY" FOR MANY OF THESE, AS WELL AS FOR FRAMINGHAM ESTABLISHED, RISK FACTORS. CORONARY VASCULAR DYSFUNCTION IS ALSO A DRIVER OF ATHEROSCLEROSIS. DESPITE ITS CRITICAL ROLE, THE TECHNOLOGY TO ASSESS THIS FUNCTION IS NOT WIDELY AVAILABLE, AS IT REQUIRES MEASURES OF CORONARY FLOW BEFORE AND DURING AN ENDOTHELIAL-DEPENDENT STIMULUS. ONE KEY GOAL OF THE NHLBI IS TO ADVANCE THE PREDICTION, PREVENTION, PREEMPTION, TREATMENT, AND CURES OF CARDIOVASCULAR DISEASES. OUR PROPOSAL IS AIMED TOWARDS COMMERCIAL DEVELOPMENT OF A CLINICALLY AVAILABLE BLOOD TEST INDICATIVE OF CORONARY VASCULAR FUNCTION, WHICH WOULD ADVANCE PERSON-SPECIFIC ASSESSMENT OF CAD RISK AND THE ABILITY OF AN INTERVENTION TO DECREASE THAT RISK. PROTEAS BIOANALYTICS, A SMALL BUSINESS CONCERN, AND JOHNS HOPKINS AIM TO DISCOVER PLASMA AND CELL PROTEOMIC SIGNATURES THAT CLOSELY CORRELATE WITH FUNCTION OF THE CORONARY VASCULATURE, THE CLINICALLY RELEVANT SITE OF CAD EVENTS. THE JOHNS HOPKINS TEAM HAS DEMONSTRATED THAT CARDIAC MAGNETIC RESONANCE IMAGING (MRI) MEASURED INCREASES IN CORONARY FLOW FOLLOWING INITIATION OF ISOMETRIC HANDGRIP EXERCISE IS DEPENDENT ON AN ENDOTHELIAL NITRIC OXIDE SYNTHASE MEDIATED INCREASE IN NITRIC OXIDE (NO). THE ADVERSE IMPACT OF RISK FACTORS COULD THEREFORE BE ATTRIBUTED TO CHANGES IN THE CONCENTRATIONS AND/OR ACTIVITIES OF NO SYNTHASE SUBSTRATES (E.G. L-ARGININE), CO-FACTORS (E.G. TETRAHYDROBIOPTERIN), ACTIVITY (PHOSPHORYLATION), AND/OR DOWNSTREAM PRODUCTS (E.G. SOLUBLE GUANYLYL CYCLASE). THE PROTEAS BIOANALYTICS TEAM DEVELOPED A STATE-OF-THE-ART PLATFORM CAPABLE OF PLASMA AND SINGLE CELL PROTEOMICS ANALYSIS. WE AIM TO USE THIS TECHNOLOGY TO MEASURE NO RELATED PATHWAYS AND EVENTUALLY DISCOVER AN ALGORITHM DESCRIBING WHICH ONE OR COMBINATION OF PATHWAY FACTORS BEST CORRELATE WITH MRI-DETERMINED CORONARY VASCULAR FUNCTION. OUR SPECIFIC AIMS FOR THIS SBIR PHASE ONE STUDY ARE: 1) TO DEMONSTRATE THE FEASIBILITY AND TECHNICAL ABILITY OF JOHNS HOPKINS TO PERFORM MRI STUDIES OF CORONARY ENDOTHELIAL FUNCTION IN SUBJECTS WITH AND WITHOUT CAD AND HENCE VARYING DEGREES OF CORONARY VASCULAR FUNCTION AND TO COLLECT BIOSPECIMENS FROM THESE PARTICIPANTS FOR SUBSEQUENT PROTEOMIC ANALYSIS. 2) TO DEMONSTRATE THE FEASIBILITY AND TECHNICAL ABILITY OF PROTEAS BIOANALYTICS TO ANALYZE THE BIOSPECIMENS OBTAINED FROM THE PARTICIPANTS STUDIED IN THE FIRST AIM AND IDENTIFY PLASMA AND CELL PROTEINS RELATED TO CORONARY VASCULAR FUNCTION. IF SUCCESSFUL, THE RESULTS WILL SUPPORT A SUBSEQUENT SBIR PHASE TWO/THREE PROGRAM TO DEVELOP A PLASMA AND CELL PROTEOMIC "SIGNATURE" THAT CHARACTERIZES CORONARY VASCULAR FUNCTION. IF ACHIEVED, THE SMALL BUSINESS CONCERN COULD THEN MARKET A CLINICALLY AVAILABLE AND EFFECTIVE BLOOD TEST TO ENHANCE THE PERSON-SPECIFIC ASSESSMENT OF CORONARY RISK AND THE ABILITY OF AN INTERVENTION TO DECREASE THAT RISK FOR HUNDREDS OF MILLIONS OF AMERICANS.