M-CSF ISOFORMS IN ATHEROSCLEROSIS

描述(改编自《调查员摘要》)：的总体目标 本研究旨在了解巨噬细胞在病因学中的作用。 集落刺激因子(M-CSF)与动脉硬化积累证据 提示M-CSF通过影响细胞的募集、生长、存活和 单核巨噬细胞的功能，可能对 促进动脉粥样硬化。支持这一结论的是 实验室最近的发现表明载脂蛋白中没有M-CSF (Apo)E或低密度脂蛋白受体缺陷小鼠显著 降低动脉粥样硬化，尽管增加了高胆固醇血症。这个 巨噬细胞集落刺激因子在动脉粥样硬化中的作用机制(S) 已知，但可能涉及M-CSF的特定亚型，其生物学效应 是由一个单一的受体介导的。总体假设是， 组织相关M-CSF亚型在致动脉粥样硬化中的表达 血管壁和骨髓中的刺激在血管病变中起关键作用 动脉粥样硬化性病变的发展。为了检验这一假设的各个方面， 建议进行的研究有以下具体目的：1)研究 血管壁巨噬细胞集落刺激因子缺乏对血管生成的影响 移植野生型造成动脉损伤。骨髓细胞植入小鼠体内 缺乏M-CSF和apoE，并通过免疫学检测确定 M-CSF的异构体由正常血管中的血管细胞和 载脂蛋白E基因缺失小鼠动脉粥样硬化形成过程；2)进行体外研究 使用培养的人和骨质疏松(OP/OP)小鼠的血管细胞 探讨M-CSF介导的生长和激活的机制(S) 单核细胞和内膜平滑肌细胞；3)生产转基因小鼠 仅在OP/OP遗传背景上表达mm-CSF亚型 研究mm-csf对动脉粥样硬化形成的影响 转基因小鼠通过高脂肪、高胆固醇饮食或将它们与 载脂蛋白E基因缺失小鼠产生在An上表达mM-CSF的复合突变体 动脉粥样硬化的背景。这些研究可能会提供新的和令人兴奋的 可能被证明对小说的合理设计有价值的信息 动脉粥样硬化的治疗干预。

DESCRIPTION (Adapted from Investigator's Abstract): The overall goal of this research is to understand the etiologic role of macrophage colony-stimulating factor (M-CSF) in atherosclerosis. Accumulating evidence suggests that M-CSF by influencing the recruitment, growth, survival and function of monocyte-macrophages, may contribute importantly to the promotion of atherosclerosis. Supporting this conclusion are this laboratory's recent findings showing that absence of M-CSF in apolipoprotein (apo) E or low density lipoprotein receptor-deficient mice significantly reduces atherosclerosis despite augmented hypercholesterolemia. The mechanism(s) underlying the causal role of M-CSF in atherosclerosis is not known, but may involve specific isoforms of M-CSF whose biological effects are mediated by a single receptor. The overall hypothesis is that augmented expression of tissue associated M-CSF isoforms in response to atherogenic stimuli in the vessel wall and bone marrow plays a critical role in the development of atheromatous lesions. To test aspects of this hypothesis, studies are proposed with the following specific aims: 1) to study the effects of M-CSF deficiency in the vessel wall on the development of arterial lesions by transplanting wild type. bone marrow cells into mice lacking both M-CSF and apoE and to determine by immunological assays which isoforms of M-CSF are expressed by vascular cells in the normal vessel and during atherogenesis in apo-E null mice; 2) to perform in vitro studies using cultured vascular cells from humans and osteopetrotic (op/op) mice to examine the mechanism(s) underlying the M-CSF mediated growth and activation of monocytes and intimal smooth muscle cells; 3) to produce transgenic mice expressing only the mM-CSF isoform on an op/op genetic background and to examine the effects of the mM-CSF on atherogenesis either by feeding the transgenic mice a high fat, high cholesterol diet or by crossing them with apo E-null mice to generate compound mutants expressing mM-CSF on an atherogenic background. These studies may provide new and exciting information that might prove valuable in the rational design of novel therapeutic interventions for atherosclerosis.