TOXIC CELLULAR DNA DAMAGE AND DISEASES

THE OBJECTIVE OF THIS PHASE I SBIR PROJECT IS TO STUDY TECHNICAL/ METHODOLOGICAL ASPECTS, PERFORMANCE CRITERIA FOR ANEW CLINICAL SPECIMEN TOXICITY TEST. STATE-OF-THE-ART FLOW CYTOMETRIC/MONOCLONAL ANTIBODY TECHNOLOGY WOULD BE USED TO DETECT DNA DAMAGE, CYTOKINETIC ABNORMALITIES, AND ANEUPLOIDY. GENOTOXICITY AND CYTOKINETIC ABNORMALITIES WOULD BE ASSESSED IN VITRO BY LABELING WITH A HALOGENERATED PHRIMIDINE (IDURD) AND THEN USING MULTIPARAMETER FLOW CYTOMETRIC ANALYSIS OF DNA CONTENT AND THE AMOUNT OF IDURD INCORPORATED (DNA REPLICATION PATTERN) VIA A FLUORESCENT TAGGED MONOCLONAL ANTIBODY HIGHLY SPECIFIC FOR IDURD. WE PROPOSE TO DEVELOP: 1) AN IMMUNOTOXICITY TEST BASED ON SHORT-TERM CULTURE, BLASTOGENEIC RESPONSE TO PHA MITOGEN STIMULATED, PERIPHERAL BLOOD LYMPHOCYTES (ULTIMATELY T-& BCELL SUBSETS); AND 2) A HEPATOTOXICITY TEST USING IN VITRO IDURD LABELING OF FINE NEEDLE ASPIRATION BIOPSIES. PHASE I STUDIES WOULD UTILIZE DOMESTIC CANINES, WHEREAS BOTH CANINE AND HUMAN CLINICAL MATERIAL WOULD BE STUDIED IN PHASE II. THE HIGH TECHNOLOGY TEST(S) TO BE DEVELOPED WOULD BE VERSATILE; HAVE BROAD COMMERCIAL AND MILITARY APPLICATIONS; AND REPRESENT A MAJOR STEP FORWARD ANALYTICALLY FOR TOXICITY TEST DETECTION OF DNA DAMAGE, CELLULAR ABNORMALITIES, AND DISEASES ACQUIRED NATURALLY OR BY EXPOSURE TO BIOLOGICAL WEAPONS.