NHLBI MINORITY INSTITUTION FACULTY MENTORED RESEARCH

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DESCRIPTION (Adapted from applicant's abstract) This application requests support for a minority school faculty development award. Training is to be undertaken in the Department of Cell and Molecular Pharmacology at the Medical University of South Carolina and will consist of attendance at departmental research seminars, tutorials, course work and a research project. One summer and one quarter per year will be devoted to the project. The proposed research will be undertaken in the laboratory of Dr. David Jollow, and will be concerned with the an aspect of the mechanisms underlying the hemolytic anemia that occurs in man and animals in response to arylamine drugs and environmental chemicals. Ongoing research in Dr. Jollow's labora-tory has indicated that: a) the hemotoxicity is due to the action(s) of metabolites (i.e., aryl hydroxylamine derivatives of the parent arylamines) rather than the parents compounds; b) that the hemolytic activity is associated with the formation of mixed protein-protein disulfides between hemoglobin and the skeletal proteins of the red cell; which c), appear to arise secondary to hydroxylamine-induced radical generation within the red cell. The chemical nature of the "primary" radicals is uncertain. The proposed studies will investigate one sub-hypothesis; viz, that the primary hemotoxin radical is the hydronitroxide derivative of the arylhydroxylamine. Specifically, a series of structurally related aryl hydroxylamines (selected on the basis of varying arylhydronitroxide stability), will be compared with respect to aryl hydronitroxide (selected on the basis of varying arylhydro-nitr-oxide stability), will be compared with respect to their hemolytic potency, methemoglobinemic activity, chemical stability and effect on red cell membrane skeletal proteins. It is expected that these studies will lead to a detailed exploration of the biology of the red cell and red cell membrane, as well as extensive experience with the experimental approaches needed to examine the relationship between membrane structure and function in blood cells. Of importance, the experience gained in basis studies or rat red cells in the mentor's laboratory (aims 1 and 2) will lead to studies in normal and glucose-6-phosphate deficient (A-) human red cells (aims 3) at the applicant's institution. This research plan is designed to expose the applicant to all facets of the experimental design and general approach to studies on the molecular basis of chemical-induced tissue injury. While the specific experiments are focused on hemolytic anemia as an endpoint, the approach is a general one which will equip the P.I. for a wide range of cardiovascular/environmental research.