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CELL SURFACE ACTIVITIES IN LIPOPROTEIN CATABOLISM

脂蛋白分解代谢中的细胞表面活性

基本信息

批准号：
6620164
负责人：
Robert Anthony Orlando
金额：
$ 29.4万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-18 至 2005-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6620164
关键词：
adipocytes blood lipoprotein metabolism blood lipoprotein transport cell differentiation genetic promoter element genetic regulatory element heparan sulfate laboratory mouse laboratory rabbit lipase low density lipoprotein receptor proteoglycan receptor binding receptor expression receptor mediated endocytosis transcription factor

项目摘要

DESCRIPTION(adapted from applicant's abstract): Studies in this application propose to investigate this apparent synergistic relationship between HSPG and LRP or megalin, that is necessary for lipoprotein/lipase clearance by cells. Using quantitative biochemical procedures we will determine if ligands are 1) transferred to the endocytic receptors for internalization following their initial binding to HSPG, or 2) if the HSPG and endocytic receptors are cointernalized with bound ligand. These studies will aid in determining if LRP and megalin can regulate ligand sequestration or lipolytic enzyme activities by controlling the amount of HSPG that is present on the cell surface through endocytosis. We also plan to identify the proteoglycan-like molecule that coprecipitates with megalin and LRP, and determine if disrupting its interactions with LRP and megalin prevents the uptake of lipoproteins by cells. As a second goal, studies are proposed to quantitatively evaluate the changes in LRP and megalin expression during adipocyte differentiation, and assess the functional role of these receptors in intracellular lipid accumulation. Supporting data have found that expression of LRP and megalin in differentiating adipocytes is responsive to glucocorticoid- and cAMP-dependent signaling pathways. Based on this observation the applicant plans to identify and characterize the cis- and trans-activating elements in the promoters of LRP and megalin that are responsible for regulating their expression levels during adipocyte development. Together, these studies will help 1) better define the functional roles of LRP and megalin in lipoprotein clearance, 2) begin to understand the molecular basis of their tissue-specific expression, and 3) advance our knowledge of cardiovascular health and disease such as atherosclerosis and obesity.

描述（改编自申请人摘要）：本申请中的研究我建议研究HSPG和 LRP或巨蛋白，其是细胞清除脂蛋白/脂肪酶所必需的。使用定量生物化学程序，我们将确定配体是否是1）转移到内吞受体进行内化后，初始结合HSPG，或2）如果HSPG和内吞受体是与结合的配体共内化。这些研究将有助于确定LRP是否并且巨蛋白可以通过以下方式调节配体螯合或脂解酶活性：控制存在于细胞表面上的HSPG的量，内吞作用我们还计划鉴定蛋白聚糖样分子，与巨蛋白和LRP共沉淀，并确定是否破坏其与LRP和megalin的相互作用阻止细胞摄取脂蛋白。作为第二个目标，建议进行研究以定量评估这些变化在脂肪细胞分化过程中LRP和megalin的表达，并评估这些受体在细胞内脂质积累中的功能作用。支持性数据已经发现，LRP和巨蛋白的表达在分化的脂肪细胞对糖皮质激素和cAMP依赖性信号通路根据这一观察，申请人计划确定并表征了LRP启动子中的顺式和反式激活元件和巨蛋白，负责调节其表达水平，脂肪细胞发育总之，这些研究将有助于1）更好地定义 LRP和巨蛋白在脂蛋白清除中的功能作用，2）开始了解其组织特异性表达的分子基础，以及3）提高我们对心血管健康和疾病的认识，动脉粥样硬化和肥胖。