MOLECULAR MECHANISMS OF CELL COMMUNICATION/ATHEROGENESIS

细胞通讯/动脉粥样硬化形成的分子机制

基本信息

批准号：
2218025
负责人：
Peter Francis Davies
金额：
$ 21.05万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-08-01 至 1996-06-30
项目状态：
已结题

项目摘要

Atherosclerosis, the underlying cause of most morbidity and mortality in the Western world, results from a focal imbalance of the normal equilibria of the artery wall. While metabolic cooperation between vascular cells is essential for the maintenance of normal artery, very little is known about the nature of cellular interactions or how they are disturbed during the recruitment of monocyte-macrophages during atherogenesis. Failure of endothelial-mediated arterial relaxation is a prominent example of communication dysfunction in hypercholesterolemia and atherosclerosis. We will examine the hypothesis that compromised gap junctional (Gj) communication in hypercholesterolemia is responsible for inhibition of vasoregulation in atherogenesis. Direct cell-cell communication occurs via Gj communicating channels through which small metabolites and ions can pass between the cytoplasmic compartments of adjacent cells. Northern blot and riboprobe hybridization analyses have demonstrated that both vascular endothelial and smooth muscle cells in tissue culture express mRNA for the Gj protein connexin 43 (cxn43). In this competing renewal, we will investigate vascular endothelial and smooth muscle cell expression of Gj proteins in situ and in vitro as a function of atherogenic processes. Lesions induced during experimental hypercholesterolemia in rabbit and baboon arteries as well as fully developed atherosclerosis in human endarterectomy tissue will be probed for Gj protein transcription and translation by in situ hybridization and immunocytochemical techniques. The spatial and temporal relationships between expression in resident endothelial and smooth muscle cells, infiltrating plasma cells, and lipid filled foam cells will be studied as a function of hypercholesterolemia. In parallel in vitro studies, the influence of altered lipid environment upon vascular cells will be evaluated in terms of RNA, protein expression and functional communication (dye transfer and electrical coupling). The effects of atherogenesis and associated changes in Gj expression and upon direct electrical coupling of vascular cells will be evaluated . A recent novel finding is that lipid-filled macrophage foam cells in human atherosclerotic lesions express mRNA for cxn43 whereas the monocytes from which they are derived do not. The proposed research will delineate the mechanisms associated with vascular cells and macrophage induction of cxn43 with particular emphasis upon the cytokine environment, the role of intracellular cholesterol accumulation, and the transcriptional, translational and signal transduction mechanisms involved. These studies will address a poorly understood mechanism of vascular cell communication at the tissue, cell and molecular level as a function of atherogenesis.

动脉粥样硬化，是最发病率和死亡率的根本原因西方世界是由于正常的焦点失衡而导致的动脉壁的平衡。而在代谢之间合作血管细胞对于维持正常动脉至关重要，非常关于细胞相互作用的性质或它们的本质知之甚少在招募单核细胞巨噬细胞期间受到干扰动脉粥样硬化。内皮介导的动脉松弛的失败是高胆固醇血症的沟通功能障碍的突出例子和动脉粥样硬化。我们将研究损害差距的假设高胆固醇血症的连接（GJ）通信负责在动脉粥样硬化中抑制血管调节。直接细胞通信通过GJ通信渠道发生小型代谢产物和离子可以通过其在细胞质之间传递相邻细胞的隔室。北印迹和肋骨探针杂交分析表明，两种血管内皮组织培养中的平滑肌细胞表达GJ蛋白的mRNA 连接蛋白43（CXN43）。在这种竞争的续约中，我们将调查 GJ蛋白的血管内皮和平滑肌细胞表达原位和体外是动脉粥样硬化过程的函数。病变在兔和狒狒实验性高胆固醇血症期间诱导动脉以及人类的动脉粥样硬化将探测内侧切除术组织的GJ蛋白转录和原位杂交和免疫细胞化学技术的翻译。居民中表达之间的空间和时间关系内皮和平滑肌细胞，浸润的浆细胞以及脂质将根据高胆固醇血症的函数研究填充的泡沫细胞。在体外研究中，脂质环境改变的影响在血管细胞上将根据RNA，蛋白表达评估和功能通信（染料转移和电耦合）。这动脉粥样硬化和GJ表达的相关变化和对将评估血管细胞的直接电耦合。最近新发现是人类中充满脂质的巨噬细胞细胞动脉粥样硬化病变表达CXN43的mRNA，而单核细胞来自它们是衍生的。拟议的研究将描绘与血管细胞和巨噬细胞诱导相关的机制 CXN43特别强调细胞因子环境，该作用细胞内胆固醇的积累和转录，涉及的翻译和信号转导机制。这些研究将解决一种知识的血管细胞机制在组织，细胞和分子水平上的通信作为动脉粥样硬化。