HEMATOPOIETIC CELLS AND LDL METABOLISM

造血细胞和低密度脂蛋白代谢

• 批准号: 3082222
• 负责人: CAROLYN L BIGELOW
• 金额: $ 6.33万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-30 至 1991-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3082222
• 关键词: atherosclerosis; blood lipoprotein metabolism; bone marrow transplantation; disease /disorder model; electron microscopy; familial hyperlipoproteinemia type II; hematopoietic stem cells; homologous transplantation; ion exchange chromatography; laboratory rabbit; leukocyte antigen typing; low density lipoprotein; molecular sieving; proteoglycan; radiation immunosuppression; radionuclide double label; receptor; tissue mosaicism

The goals of the proposed study include the measurement of metabolic abnormalities of hematopoietic cells in the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of familial hypercholesterolemia (FH) in man, and the determination of the effects of transplantation of normal hematopoietic cells on lipid metabolism and the development of atherosclerosis in the WHHL rabbit. Hematopoietic cells of WHHL rabbits exhibit metabolic abnormalities including the absence of low density lipoprotein (LDL) receptors and abnormal production of proteoglycans which have been implicated in the pathogenesis of atherosclerosis. Using long term bone marrow cultures form normal and WHHL rabbits we plan to more specifically define the abnormalities in LDL metabolism by measuring receptor-dependent metabolism over time. Proteoglycan biosynthesis will be assayed using combinations of DEAE ion exchange chromatography, molecular sieve chromatography, and electron microscopy. We will determine the requirements for the development of complete hematopoietic chimerism in the rabbit following which allogeneic bone marrow transplantation (BMT) between normal NZW rabbit donors and homozygous WHHL rabbit recipients will be carried out. After the construction of complete NZW/WHHL chimeras, we will measure in vivo LDL metabolism in BMT recipients by using a double radioisotope labeling technique to determine the plasma clearance of LDL. We will also determine the impact of transplantation of normal marrow into WHHL recipients by pathologically examining arteries for evidence of atherosclerosis in some recipients and following others for long term survival. The candidate is committed to the establishment of a career in academic medicine as a laboratory-based investigator. The University of Washington faculty provides a unique blend of investigators with expertise in essentially all aspects of the proposed research project; and the facilities at the Fred Hutchinson Cancer Research Center will provide all the necessary equipment for the accomplishment of the proposed research.

拟议研究的目标包括新陈代谢的测量。 可遗传的渡边人的造血细胞异常 家族性高脂血症动物模型的建立 人高胆固醇血症(FH)及其治疗作用的研究 正常造血细胞移植对脂代谢的影响及其机制 WHHL兔动脉粥样硬化的研究进展。人的造血细胞 WHHL兔表现出代谢异常，包括Low缺失 密度脂蛋白受体与血管内皮生长因子的异常产生 蛋白多聚糖与多发性硬化症的发病机制 动脉硬化。使用长期骨髓培养形成正常和WHHL 我们计划更具体地定义低密度脂蛋白的异常 通过测量随时间推移的受体依赖的新陈代谢。 蛋白多糖的生物合成将使用DEAE离子的组合进行检测 交换层析、分子筛层析和电子 显微镜。我们将确定发展的要求 兔完全的造血嵌合体，随后是同种异体 正常新西兰兔供体与供体间的骨髓移植 将进行纯合子WHHL兔移植。后 构建完整的NZW/WHHL嵌合体，我们将在体内测量低密度脂蛋白 应用双重放射性同位素标记研究骨髓移植受者的代谢 测定低密度脂蛋白血浆清除率的技术。我们还将确定 正常骨髓移植对WHHL受者的影响 对动脉进行病理检查，以寻找动脉粥样硬化的证据 接受者和追随他人以求长期生存。 这位候选人致力于在学术界建立自己的事业 医学作为一名以实验室为基础的研究员。华盛顿大学 学院提供了一支独特的研究人员队伍，他们具有以下专业知识 基本上是拟议研究项目的所有方面；以及 弗雷德·哈钦森癌症研究中心的设施将提供所有 完成拟议研究所需的设备。