The Role of ABCC6 In Chronic & Acute Cardiovascular Mineralization

描述（由申请人提供）：异常矿化发生在几种常见疾病的背景下，包括高龄、糖尿病、高胆固醇血症、慢性肾衰竭和某些遗传疾病。ABCC 6基因的功能丧失突变会导致弹性假黄瘤（PXE）和营养不良性心脏钙化（DCC）等疾病中慢性或急性形式的营养不良性矿化。这些病理的特征在于心血管和/或皮肤组织的矿化。PXE是可遗传的，而DCC是由心血管损伤引起的获得性表型。我们已经获得的初步数据表明，ABCC 6启动和调节钙化抑制剂途径，在急性和慢性营养不良性钙化中起着至关重要的作用。我们推测，肝脏ABCC 6功能的丧失直接或通过循环因子水平的增加或修饰而导致心血管组织中钙化调节剂的失衡。为了验证这一假设，我们将使用小鼠模型来表征ABCC 6突变对蛋白质结构和功能的影响，确定Abcc 6-/-小鼠对急性缺血性心脏损伤的反应，并确定Abcc 6-/-在动脉粥样硬化斑块钙化中的作用。

DESCRIPTION (provided by applicant): Abnormal mineralization occurs in the context of several common conditions, including advanced age, diabetes, hypercholesterolemia, chronic renal failure and certain genetic conditions. Loss-of-function mutations in the ABCC6 gene cause chronic or acute forms of dystrophic mineralization in diseases such as Pseudoxanthoma elasticum (PXE) and dystrophic cardiac calcification (DCC). These pathologies are characterized by mineralization of cardiovascular and/or dermal tissues. PXE is heritable while DCC is an acquired phenotype resulting from cardiovascular insults. We have obtained preliminary data that suggest that ABCC6 initiates and modulates a calcification inhibitor pathway with a crucial role in both acute and chronic dystrophic calcification. We hypothesize that the loss of ABCC6 function in liver produces an imbalance of modulators of calcification in cardiovascular tissues either directly or through increased levels or modification of a circulating factor. To test this hypothesis, we will use a mouse models to characterize the effects of ABCC6 mutations on the structure and function of the protein, determine the response of Abcc6-/- mice to acute ischemic cardiac injuries and determine the role of Abcc6-/- in the calcification of the atherosclerotic plaque.