NHLBI MINORITY INSTITUTION FACULTY MENTORED RESEARCH

描述 （改编自申请人摘要）本申请要求支持 少数民族学校教师发展奖。 培训将在以下方面进行： 医科大学细胞与分子药理学系 南卡罗来纳州，并将包括出席部门研究 研讨会、辅导、课程作业和研究项目。 一个夏天和一个 每年有四分之一的时间用于该项目。 拟议中的研究将在大卫博士的实验室进行 Jollow，并将关注机制的一个方面 导致人类和动物出现溶血性贫血 芳香胺药物和环境化学品。 正在进行的研究在博士。 Jollow实验室的研究表明：a）血液毒性是由于 代谢物的作用（即，母体的芳基羟胺衍生物 芳基胺）而不是母体化合物; B）溶血性化合物 活性与混合蛋白质-蛋白质的形成有关 血红蛋白和红细胞骨架蛋白之间的二硫化物; 其中c），似乎出现继发于羟胺诱导的自由基 在红细胞内生成。 “初级”的化学性质 激进分子不确定。 拟议的研究将调查一个 亚假设;即，主要的血毒素自由基是 芳基羟胺的氢氧化氮衍生物。 具体来说，一系列 结构上相关的芳基羟胺（基于 不同的芳基氢氮氧化物稳定性），将相对于芳基 氢氮氧化物（基于不同的芳基氢氮氧化物选择 稳定性），将比较它们的溶血效力， 高铁血红蛋白活性、化学稳定性和对红细胞的影响 膜骨架蛋白 预计这些研究将导致 详细探索红细胞和红细胞膜的生物学， 以及所需实验方法的丰富经验， 检查血液中膜结构和功能之间的关系 细胞 重要的是，在基础研究或老鼠红中获得的经验 导师实验室的细胞（目标1和2）将导致研究， 正常和葡萄糖-6-磷酸缺乏（A-）的人红细胞（目标3）. 申请人的机构。 本研究计划旨在使申请人接触到 实验设计和分子基础研究的一般方法 化学物质引起的组织损伤 虽然具体的实验是 该方法侧重于将溶血性贫血作为终点， 可以让私家侦探用于广泛的心血管/环境 research.

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.