MOLECULAR MECHANISMS CELL COMMUNICATIONS/ATHEROGENESIS

动脉粥样硬化，是中国大多数发病率和死亡率的根本原因 西方世界，是正常情况下焦点失衡的结果 动脉壁的平衡。而新陈代谢的合作 血管细胞对维持正常的动脉是必不可少的，非常 关于细胞相互作用的性质或它们是如何形成的，人们知之甚少 在单核-巨噬细胞募集过程中受到干扰 动脉粥样硬化的形成。内皮介导的动脉松弛失败是 高胆固醇血症中沟通障碍的一个突出例子 和动脉粥样硬化。我们将检验折衷GAP的假设 高胆固醇血症的交界性(GJ)通讯是 动脉粥样硬化形成中血管调节的抑制。 细胞间的直接通信通过GJ通信通道进行 小的代谢物和离子可以通过它在细胞质之间传递 相邻细胞的隔间。Northern印迹和核探针 杂交分析表明，两种血管内皮细胞 组织培养中的平滑肌细胞表达GJ蛋白的mRNA 连接蛋白43(Cxn43)。在这场竞争的更新中，我们将调查 血管内皮细胞和平滑肌细胞中GJ蛋白的表达 在体内和体外作为动脉粥样硬化形成过程的函数。损伤 实验性高胆固醇血症所致的兔和狒狒 人类动脉以及完全发展的动脉粥样硬化 动脉内膜切除术组织将被检测GJ蛋白转录和 通过原位杂交和免疫细胞化学技术进行翻译。 城市居民情绪表达的时空关系研究 血管内皮细胞和平滑肌细胞、浸润性浆细胞和脂质 充盈的泡沫细胞将作为高胆固醇血症的函数进行研究。 在平行的体外研究中，脂类环境改变的影响 对血管细胞的影响将通过RNA、蛋白质的表达进行评估 和功能通讯(染料转移和电耦合)。这个 动脉粥样硬化形成及相关GJ表达变化的影响 将对血管细胞的直接电耦合进行评估。最近 新发现是人类体内充满脂质的巨噬细胞泡沫细胞 动脉粥样硬化病变表达cxn43的mRNA，而单核细胞 而它们并不是派生出来的。拟议的研究将勾勒出 血管细胞和巨噬细胞诱导血管生成的机制 Cxn43，特别强调细胞因子环境，作用 细胞内胆固醇的积累，以及转录的， 涉及翻译和信号转导机制。 这些研究将解决一个鲜为人知的血管细胞机制。 在组织、细胞和分子水平上的通信作为 动脉粥样硬化的形成。

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.