M-CSF ISOFORMS IN ATHEROSCLEROSIS

描述（改编自研究者摘要）：总体目标 本研究旨在了解巨噬细胞的致病作用， 集落刺激因子（M-CSF）在动脉粥样硬化中的作用。 越来越多的证据 提示M-CSF通过影响细胞的募集、生长、存活和 单核细胞-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 实验室最近发现表明载脂蛋白中不存在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，尽管增加高胆固醇血症。 的 M-CSF在动脉粥样硬化中的因果作用的潜在机制不是 已知，但可能涉及M-CSF的特定同种型，其生物学效应 都是由单一受体介导的 总的假设是， 组织相关M-CSF亚型在致动脉粥样硬化反应中的表达 血管壁和骨髓中的刺激在 动脉粥样硬化病变的发展。 为了验证这一假设， 建议的研究有以下具体目标：1）研究 血管壁M-CSF缺乏对血管内皮细胞生长发育的影响 移植野生型的动脉病变。 小鼠骨髓细胞 缺乏M-CSF和apoE，并通过免疫学测定来确定， M-CSF的同种型由正常血管中的血管细胞表达， 在apo-E基因敲除小鼠动脉粥样硬化形成过程中; 2）进行体外研究 使用来自人和骨硬化（OP/OP）小鼠的培养的血管细胞， 检查M-CSF介导的生长和激活的潜在机制 单核细胞和内膜平滑肌细胞; 3）产生转基因小鼠 在op/op遗传背景下仅表达mM-CSF同种型， 检查mM-CSF对动脉粥样硬化形成的影响， 转基因小鼠高脂肪，高胆固醇饮食，或通过杂交， apo E-敲除小鼠，以产生在细胞表面表达mM-CSF的复合突变体。 致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.