Genetic Regulation of Arterial Wall by Canonical Wnt Signaling

描述(由申请人提供)： 摘要：在美国，冠状动脉疾病(CAD)及其后果仍然是最大的死亡原因。流行病学研究已经确定了几个危险因素在冠状动脉疾病(CAD)中的关键作用。然而，在疾病人群和对照人群之间，已建立的冠心病危险因素的范围和严重程度有显著的重叠。这表明，普通人群中的这种疾病不能仅由这些风险因素来解释，并留下了如何识别新的风险因素的问题。通过一系列研究，我们最近发现了Wnt共同受体LRP6(LRP6R611C)的功能缺失突变，它是一种孟德尔形式的冠心病、糖尿病和代谢综合征的基础。该突变的特征表明，它损害了配体结合，降低了LRP6的磷酸化和核β-连环素对Wnt刺激的定位，从而损害了Wnt下游信号。自从我们最初发现Wnt信号受损以来，在多项临床和实验研究中，Wnt信号受损已被证明是冠心病的危险因素。这种疾病基因的发现及其与改变的典型Wnt信号的联系为鉴定新的疾病途径提供了一个难得的机会。通过同源重组，我们产生了LRP6R611C突变的小鼠。LRP6R611C小鼠复制了大多数人类表型，包括高脂饮食下的动脉内膜增生，并在疾病等位基因纯合时发展为极度弥漫性和增殖性CAD。我们建议：(1)确定新生内膜细胞的来源；(2)研究“规范的”Wnt-catenin信号在新生内膜形成中的作用；(3)通过命运定位、遗传挽救和骨髓嵌合体的产生，评估骨髓来源细胞(BMD)在新生内膜形成中的作用。

DESCRIPTION (provided by applicant): Abstract: Coronary artery disease (CAD) and its consequences remain the single largest cause of death in the United States. Epidemiologic studies have established the key roles of several risk factors for coronary artery disease (CAD). However, there is significant overlap in extent and severity of established CAD risk factors between disease and control populations. This suggests that the disease in the general population cannot be accounted for by these risk factors alone and leaves open the question of how to identify novel risk factors. Through a series of studies, we recently identified a loss of function mutation in the Wnt co-receptor LRP6 (LRP6R611C) that underlies a Mendelian form of coronary artery disease, diabetes and metabolic syndrome. The characterization of the mutation has shown that it impairs ligand binding, reduces LRP6 phosphorylation and nuclear beta-catenin localization in response to Wnt stimulation, and subsequently impairs downstream Wnt signaling. Since our initial discovery, impaired Wnt signaling has shown to be a risk factor for CAD in multiple clinical and experimental studies. Discovery of this disease gene and its link to altered canonical Wnt signaling has provided an exceptional opportunity for identification of novel disease pathways. Through homologous recombination, we have generated mice with the LRP6R611C mutation. LRP6R611C mice replicate most human phenotypes, including arterial intimal hyperplasia on high fat diet and develop extremely diffuse and proliferative CAD when they are homozygote for the disease allele. We propose ( 1) to determine the origin of the neointimal cell (2) to examine the role of "canonical" Wnt-catenin signaling in neointima formation and (3) to assess the contribution of bone marrow derived cells (BMD) to neointima formation, by fate mapping, genetic rescue and generation of bone marrow chimeras.