Interfacial Macromolecular Transport and Metabolism of LDL in the Arterial Intima

在这个建议中，一个新的假设，提出了当地 动脉粥样硬化形成的起源，试图将局部变化与 大分子对事件详细顺序的渗透性 以及导致泡沫细胞损伤形成的机制。 的 这一假设为以下关系提供了一种可能的解释： 动脉壁细胞更新，大分子通透性，受体 介导动脉内膜细胞成分的代谢 和媒体，招聘和内皮下 血液传播的单核细胞的渗透和运输及其 转化为巨噬细胞型泡沫细胞。 时间相关 主要研究人员开发的模型显示， 内皮大分子之间的定量关系 渗透性和渗漏连接， 不频繁的细胞将进一步发展， 包括：（1）用于内部的离散扩散阻挡层 弹性膜，（2）上皮间裂隙中的对流， 内皮下组织和（3）受体介导的模型 低密度脂蛋白（LDL）代谢的内皮和 平滑肌细胞 （3）中的定量模型将是 基于Brown和Goldstein的实验模型， 低密度脂蛋白受体介导的代谢和细胞内调节 它们在人成纤维细胞中的数量密度。 简化 数学模型已经制定了六个关键 控制这种调节的过程，其中， 各个过程由可用的实验确定。 这些模型的目的是获得一个定量的 细胞外天然低密度脂蛋白 浓度，水解的游离胆固醇含量， 细胞和受体数量的调节。 内皮下 然后将由整体模型预测的LDL浓度与 释放趋化因子进行募集， 基于定量的血液传播单核细胞的粘附 新假设中提出的标准。 进行的实验 在一个补充NIH赠款最近证实了第一个 假设的一部分表明，低密度脂蛋白的泄漏通过 内皮细胞通过周围的不良连接发生， 细胞数量很少。 进一步的实验 需要验证以下内容之间的定量联系： 内皮下LDL水平和单核细胞募集 新的假设。

In this proposal, a new hypothesis is advanced for the local origin of atherogenesis which attempts to relate local changes in macromolecular permeability to the detailed sequence of events and mechanisms leading to the formation of the foam cell lesion. The hypothesis offers a possible explanation for the relationship between arterial wall cell turnover, macromolecular permeability, the receptor mediated metabolism of the cellular component of the arterial intima and media, the recruitment and subendothelial penetration and transport of blood borne monocytes and their conversion to macrophage type foam cells. The time dependent model developed by the principal investigators to show the quantitative relationship between endothelial macromolecular permeability and leaky junctions associated with statistically infrequent cells in turnover will be further developed to include: (1) a discrete diffusion barrier for the internal elastic lamina, (2) convection in the interendothelial clefts and subendothelial tissue and (3) models for the receptor mediated low density lipoprotein (LDL) metabolism of the endothelial and smooth muscle cells. The quantitative models in (3) will be based on the experimental model of Brown and Goldstein for the LDL receptor mediated metabolism and the intracellular regulation of their number density in human fibroblasts. Simplified mathematical models have been formulated for the six key processes governing this regulation wherein the constants in the individual processes are determined from available experiments. The objective of these models is to obtain a quantitative predictive relationship between the extracellular native LDL concentration, the hydrolyzed free cholesterol content of the cells and the regulation of receptor number. The subendothelial LDL concentration predicted by the overall model is then related to the release of chemotactic factors for the recruitment and adhesion of blood borne monocytes based on the quantitative criteria proposed in the new hypothesis. Experiments conducted in a complementary NIH grant have recently confirmed the first part of the hypothesis showing that the leakage of LDL across the endothelium does occur via poorly formed junctions surrounding the small population of cells in turnover. Further experiments are required to validate the quantitative link between subendothelial LDL levels and monocyte recruitment proposed in the new hypothesis.