Genetic Regulation of Arterial Wall by Canonical Wnt Signaling

描述（由申请人提供）： 翻译后摘要：冠状动脉疾病（CAD）及其后果仍然是单一的最大的死亡原因在美国。流行病学研究已经确定了几个危险因素对冠状动脉疾病（CAD）的关键作用。然而，在疾病和对照人群之间，已确定的CAD风险因素的程度和严重程度存在显著重叠。这表明，普通人群中的疾病不能仅由这些风险因素来解释，并留下了如何识别新风险因素的问题。通过一系列研究，我们最近发现了Wnt辅助受体LRP 6（LRP 6 R611 C）的功能缺失突变，该突变是冠状动脉疾病、糖尿病和代谢综合征的孟德尔形式的基础。突变的表征表明，它损害配体结合，减少LRP 6磷酸化和核β-连环蛋白定位响应Wnt刺激，并随后损害下游Wnt信号传导。自我们最初发现以来，在多项临床和实验研究中，受损的Wnt信号转导已被证明是CAD的风险因素。这种疾病基因的发现及其与改变的经典Wnt信号传导的联系为鉴定新的疾病途径提供了一个特殊的机会。通过同源重组，我们已经产生了具有LRP 6 R611 C突变的小鼠。LRP 6 R611 C小鼠复制大多数人类表型，包括高脂饮食下的动脉内膜增生，并且当它们是疾病等位基因的纯合子时，发展出极度弥漫性和增殖性CAD。我们建议（1）确定新生内膜细胞的起源（2）检查“典型”Wnt/β-连环蛋白信号传导在新生内膜形成中的作用和（3）通过命运作图、遗传拯救和骨髓嵌合体的产生来评估骨髓衍生细胞（BMD）对新生内膜形成的贡献。

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/ß-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.