HEMATOPOIETIC CELLS AND LDL METABOLISM

造血细胞和低密度脂蛋白代谢

• 批准号: 3082223
• 负责人: CAROLYN L BIGELOW
• 金额: $ 4.23万
• 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/3082223
• 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测量代谢 渡边遗传性造血细胞异常 高脂血症（WHHL）兔，一种家族性动物模型 人类高胆固醇血症（FH）及其影响的测定 正常造血细胞移植对脂质代谢的影响 WHHL 兔动脉粥样硬化的发展。 造血细胞 WHHL 兔子表现出代谢异常，包括缺乏低水平 密度脂蛋白（LDL）受体和异常产生 与发病机制有关的蛋白多糖 动脉粥样硬化。 使用正常和 WHHL 的长期骨髓培养 我们计划更具体地定义兔子的 LDL 异常 通过测量受体依赖性代谢随时间的变化来进行代谢。 将使用 DEAE 离子组合来测定蛋白聚糖生物合成 交换色谱法、分子筛色谱法、电子色谱法 显微镜。 我们将确定开发的要求 兔体内完全造血嵌合，随后进行同种异体 正常 NZW 兔供体和 将进行纯合 WHHL 兔子受体。 之后 构建完整的 NZW/WHHL 嵌合体，我们将测量体内 LDL 使用双放射性同位素标记进行 BMT 接受者的代谢 测定 LDL 血浆清除率的技术。 我们还将确定 将正常骨髓移植到 WHHL 受者体内的影响 对某些人的动脉进行病理学检查以寻找动脉粥样硬化的证据 接受者并跟随其他人以实现长期生存。 候选人致力于建立学术生涯 医学作为实验室研究者。 华盛顿大学 教师提供了具有以下专业知识的独特研究人员组合 基本上拟议研究项目的所有方面；和 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。