HEMATOPOIETIC CELLS AND LDL METABOLISM

拟议研究的目标包括测量代谢 Watanabe遗传性造血细胞异常 高脂血症（WHHL）家兔，一种家族性高脂血症动物模型 高胆固醇血症（FH）的人，并确定的影响， 正常造血细胞移植对脂质代谢的影响及 WHHL兔动脉粥样硬化的发展。 造血细胞 WHHL兔表现出代谢异常，包括缺乏低水平的 密度脂蛋白（LDL）受体和异常生产的 蛋白聚糖，其已经涉及的发病机制， 动脉粥样硬化 使用正常和WHHL骨髓长期培养 我们计划更具体地定义LDL的异常， 通过测量随时间推移的受体依赖性代谢来测定代谢。 蛋白聚糖的生物合成将使用DEAE离子 交换色谱法、分子筛色谱法和电子 显微镜 我们将确定发展的要求， 完全造血嵌合体在兔，随后同种异体 正常NZW兔供体与 将进行纯合WHHL兔受体。 后 构建完整的NZW/WHHL嵌合体，我们将测量体内LDL 用放射性同位素双标记法研究骨髓移植受者的代谢 技术来确定LDL的血浆清除率。 我们还将确定 正常骨髓移植入WHHL受者的影响， 病理学检查动脉以寻找动脉粥样硬化的证据， 接受者和跟随其他人长期生存。 候选人致力于建立学术生涯 医学作为一个实验室为基础的调查。 华盛顿大学 教师提供了一个独特的混合调查与专业知识， 建议研究项目的基本所有方面;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。

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.