DISTINCT HUMAN MACROPHAGE RECEPTOR FOR ABNORMAL VLDL

动脉粥样硬化引起的心血管疾病是 美国将面临死亡。单核-巨噬细胞(MM)来源的、充满脂肪的“泡沫” “细胞”既是早期脂肪条纹的特征，也是后来容易破裂的特征， 血栓形成的损伤。血浆甘油三酯升高[高(H)甘油三酯，空腹 或餐后]是动脉粥样硬化性血栓性疾病的新的危险因素； 机制上的联系尚不清楚。一种可能的机制是通过MM 受体(R)我们发现与富含甘油三酯的脂蛋白的载脂蛋白B结合 (TGRLP)，包括乳糜粒载脂蛋白B-48(CM)，诱导泡沫细胞 体外与体内动脉粥样硬化病变和骨骼中的相似 患有持续性CMS和残留物的人的骨髓、皮肤和脾。我们 克隆了人R‘s基因(3773bp)。它编码了一个新的、唯一的R 诱导TGRLP摄取和泡沫细胞的形成 CHO-K1细胞阴性。其约3.8kb的mRNA在THP-1中表达 单核细胞，胎盘，外周血单核细胞，骨髓， 脾、扁桃体、淋巴结、阑尾呈泡沫状分布 持续性CMS患者体内的细胞。免疫组织化学研究 显示R在人主动脉脂肪条纹泡沫细胞中的表达 冠状动脉和颈动脉病变及免疫组织多发性骨髓瘤。我们假设 受体的正常作用是确保有效地传递必需的 饮食中的脂质和脂溶维生素对单核细胞和可获得的 免疫系统的巨噬细胞；当不堪重负时，如在 持续性CMS，参与泡沫细胞的形成和动脉粥样硬化的形成。 为了在体内验证这一假说，在小鼠体内进行了同源重组 胚胎干细胞将被用来使R缺乏(R-/-和R-/+) 小鼠和组织特异性的、过度表达的转基因。基因效应 剂量对脂蛋白谱和动脉粥样硬化易感性的影响 并与小鼠动脉粥样硬化模型(apoE-/-，LDLR-/-)杂交 和HTG(apoCIII和apoCI转基因)将有助于澄清这个R的作用 体内脂蛋白代谢和动脉粥样硬化的研究。人的体外研究 单核细胞和转基因CHO将定义R的机制 核心脂的合成、加工、循环和吸收。潜力 这一R对心血管疾病的影响证明拟议的研究提供了细胞， 治疗的分子和体内功能原理 干预措施。

Cardiovascular disease (CVD) due to atherosclerosis is the major cause of death on the US. Monocyte-macrophage (MM)-derived, lipid-filled "foam cells" are hallmarks of both early fatty streak and later, rupture-prone, thrombogenic lesions. Elevated plasma triglycerides [hyper (H) TG, fasting or post-prandial] are emerging risk factors for atherothrombotic disease; the mechanistic links are not known. One potential mechanism is via a MM receptor (R) we identified that binds apoB of TG-rich lipoproteins (TGRLP), including apoB-48 of chylomicrons (CM), inducing foam cells in vitro like those in vivo in atherosclerotic lesions and in the bone marrow, skin, and spleen in humans with persistent CMs and remnants. We have cloned the human R's cDNA (3773 bp). It encodes a new, unique R that induces TGRLP uptake and foam cell formation when transfected into R- negative CHO-K1 cells. Its approximately 3.8 kb mRNA is expressed in THP-1 monocytes, placenta, peripheral mononuclear leukocytes, bone marrow, spleen, tonsil, lymph node, and appendix, a distribution like that of foam cells in vivo in humans with persistent CMs. Immunohistochemical studies show R expression in foam cells of human aortic fatty streaks, advanced coronary and carotid lesions and MM of immune tissues. We hypothesize that the receptor's normal role is to ensure efficient delivery of essential dietary lipids and lipid-soluble vitamins to monocytes and accessible macrophages of the immune system; when overwhelmed, as in states with persistent CMs, it is involved in foam cell formation and atherogenesis. To test this hypothesis in vivo, homologous recombination in murine embryonic stem (ES) cells will be used to make R deficient (R-/- and R-/+) mice and tissue specific, over-expressing transgenics. Effects of gene dosage on lipoprotein profiles and atherosclerosis susceptibility in these and in crosses with murine models of atherosclerosis (apoE-/-, LDLR-/-) and HTG (apoCIII, and apoCI transgenics) will help clarify this R's role in lipoprotein metabolism and atherogenesis in vivo. Studies in vitro in monocytes and transfected CHOs will define mechanisms of the R's synthesis, processing, cycling, and uptake of core lipids. The potential impact of this R on CVD warrants the proposed studies to provide cellular, molecular, and in vivo functional rationales for therapeutic interventions.