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Mechanisms of p42/44MAPK-induced LDL receptor expression

p42/44MAPK诱导LDL受体表达的机制

基本信息

批准号：
6773909
负责人：
KAMAL D MEHTA
金额：
$ 25.81万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2006-08-31
项目状态：
已结题

项目摘要

Of all known risk factors promoting coronary artery disease, a high serum low density lipoprotein (LDL) level is the most important. The regulation of hepatic LDL receptor expression is a potential mechanism by which dietary and humoral factors alter plasma LDL levels, and upregulation of LDL receptor expression is the basis for current treatment of hypercholesterolemia. The negative regulation of LDL receptor transcription by sterols has been extensively delineated; however, the molecular mechanisms of induction and the signaling cascades controlling activity of critical nuclear factor(s) are not known. Recently, we provided the first evidence that specific activation of the p42/44mitogen-activated protein kinase (MAPK) is not only required but is sufficient to fully induce LDL receptor expression. Our recent observations supporting the requirement of CREB-binding protein (CBP) in p42/44MAPK-induced LDL receptor transcription are the basis of Specific Aim 1, and the studies proposed will link CBP acetyltransferase activity with modification of sterol responsive element binding proteins (SREBPs) and/or chromatin remodeling in the promoter region. Effects of CBP-SREBP protein-protein interactions on transactivation and on chromatin structures during the induction process will be examined by using a p42/44MAPK-responsive mammalian two-hybrid system and in vivo footprinting techniques. The Specific Aim 2 will study interleukin-1beta- and hepatocyte growth factor-induced LDL receptor expression to examine how p42/44MAPK participates during induction by sterol-sensitive and sterol-independent mechanisms. The Specific Aim 3 will establish a negative relationship between stress-activated p38MAPK alpha- isoform and LDL receptor expression and then examine the role of p38MAPK activation in stress-induced hypercholesterolemia through suppression of LDL receptor expression. This aim is based on our observation that specific inhibition of p38MAPK alpha-isoform induces LDL receptor expression via suppression of p42/44MAPK. Finally, in light of the crucial roles of MAPKs in hepatic cells, the Specific Aim 4 will examine the roles of p42/44MAPK and p38MAPK cascades in regulating expression of LDL and scavenger receptors that are a critical determinant of lipid accumulation in the macrophages and their conversion to foam cells. Defining the molecular mechanisms and the signaling pathways regulating the induction process will help in understanding the pathologic states under which the receptor pathways are perturbed, resulting in hypercholesterolemia. This knowledge could be exploited to develop improved hypercholesterolemia therapies and to reduce foam cell formation.

在所有已知的促进冠状动脉疾病的危险因素中，高血清低密度脂蛋白（LDL）水平是最重要的。肝脏LDL受体表达的调节是饮食和体液因素改变血浆LDL水平的潜在机制，而LDL受体表达的上调是目前治疗高胆固醇血症的基础。甾醇对LDL受体转录的负调控已被广泛描述；然而，诱导的分子机制和控制关键核因子活性的信号级联尚不清楚。最近，我们提供了第一个证据，证明p42/44丝裂原活化蛋白激酶（MAPK）的特异性激活不仅是必需的，而且是充分诱导LDL受体表达的。我们最近的观察结果支持在p42/ 44mapk诱导的LDL受体转录中需要creb结合蛋白（CBP），这是Specific Aim 1的基础，并且提出的研究将CBP乙酰转移酶活性与甾醇反应元件结合蛋白（SREBPs）的修饰和/或启动子区域的染色质重塑联系起来。在诱导过程中，CBP-SREBP蛋白-蛋白相互作用对转激活和染色质结构的影响将通过p42/ 44mapk响应的哺乳动物双杂交系统和体内足迹技术进行研究。Specific Aim 2将研究白细胞介素-1 β和肝细胞生长因子诱导的LDL受体表达，以研究p42/44MAPK如何通过胆固醇敏感和胆固醇非依赖性机制参与诱导过程。Specific Aim 3将建立应激激活的p38MAPK α -异构体与LDL受体表达之间的负相关关系，然后通过抑制LDL受体表达来研究p38MAPK激活在应激诱导的高胆固醇血症中的作用。这一目的是基于我们的观察，特异性抑制p38MAPK α -异构体通过抑制p42/44MAPK诱导LDL受体表达。最后，鉴于mapk在肝细胞中的关键作用，Specific Aim 4将研究p42/44MAPK和p38MAPK级联在调节LDL和清除率受体表达中的作用，而LDL和清除率受体是巨噬细胞中脂质积累及其向泡沫细胞转化的关键决定因素。明确分子机制和调节诱导过程的信号通路将有助于理解受体通路被扰乱导致高胆固醇血症的病理状态。这一知识可以用来开发改进的高胆固醇血症治疗和减少泡沫细胞的形成。