Translational Studies of ADAMTS7 a Novel GWAS Locus for Coronary Atherosclerosis

描述(申请人提供)：动脉粥样硬化性冠状动脉疾病(CAD)仍然是导致死亡和残疾的主要原因。需要新的生物学发现来改变我们对这种疾病的理解，并推动临床和治疗方面的进步。在最近的全基因组关联研究中确定的CAD基因座中，许多与已建立的危险因素或已知的动脉粥样硬化机制没有明显的关联。然而，很少有新的基因座具有明确的候选基因、可信的生物学和暗示特定翻译假设的初步证据的组合。通过GWAS，我们发现并复制了ADAMTS7作为一个新的冠状动脉粥样硬化基因。这一发现在另外两项大规模的全球气候变化倡议中也得到了重现。ADAMTS7与传统的危险因素无关。然而，这种金属蛋白酶在人血管平滑肌细胞(VSMC)和动脉粥样硬化病变中表达，我们的初步研究表明，小鼠Adamts7/-基因缺失降低了体内对股动脉损伤的新生内膜反应。我们推测，ADAMTS7通过裂解软骨寡聚基质蛋白(COMP)促进向VSMC合成表型的转变，加速动脉粥样硬化。COMP是一种内源性的VSMC迁移、增殖和基质分泌的刹车。在这里，我们提出了一系列实验：(1)确定COMP的ADAMTS7结构功能，并建立高通量的用于小鼠和人类的ADAMTS7活性测定；(2)检测ADAMTS7的胚系功能丧失(LOF)和功能获得(GOF)对小鼠VSMC表型、血管损伤和动脉粥样硬化的影响；(3)探讨人类罕见和低频率非同义ADAMTS7等位基因的功能影响和CAD相关性。我们的研究团队处于有利地位，可以执行这些翻译研究，并促进我们对ADAMTS7在动脉粥样硬化中作用的原因、方向性和机制的理解。

DESCRIPTION (provided by applicant): Atherosclerotic coronary artery disease (CAD) remains a major cause of death and disability. New biological discoveries are required to transform our understanding of the disease and to spur clinical and therapeutic advances. Of CAD loci identified through recent genome wide association studies (GWAS), many have no apparent association with established risk factors or known mechanisms of atherosclerosis. Few new loci, however, have the combination of a clear candidate gene at the locus, plausible biology, and preliminary evidence that suggest specific translational hypotheses. Through GWAS, we discovered and replicated ADAMTS7 as a novel locus for coronary atherosclerosis. This finding has been reproduced in two other large-scale GWAS initiatives. ADAMTS7 has no relationship to traditional risk factors. This metalloproteinase, however, is expressed in human vascular smooth muscle cell (VSMC) and atherosclerotic lesions and our preliminary studies suggest that Adamts7-/- gene deletion in mice reduces the in vivo neointimal response to femoral artery injury. We hypothesize that ADAMTS7 promotes transition to VSMC synthetic phenotype and accelerates atherosclerosis by cleaving cartilage oligomeric matrix protein (COMP) an endogenous brake on VSMC migration, proliferation and matrix secretion. Here, we propose a series of experiments to: (Aim 1) define ADAMTS7 structure-function for COMP and develop a high-throughput ADAMTS7 activity assay for use in mouse and human, (Aim 2) examine effects of germline loss-of-function (LOF) and gain-of-function (GOF) of Adamts7 on VSMC phenotype, vascular injury and atherosclerosis in mouse models, and (Aim 3) interrogate functional impact and CAD association of rare and low frequency non-synonymous ADAMTS7 alleles in human. Our investigative team is well positioned to execute these translational studies and advance our understanding of causation, directionality and mechanisms of ADAMTS7 action in atherosclerosis.