Prevention of Vascular Calcification In Chronic Kidney Disease

 描述(申请人提供)：血管和心脏瓣膜的钙化是一个严重的问题，没有特殊的治疗方法。我们的研究表明，细胞外焦磷是一种关键的内源性钙化抑制物，可能缺乏与血管钙化相关的条件，可以预防钙化。然而，细胞外焦磷酸盐的代谢和治疗潜力都不是完全了解的。这项研究的长期目标是开发基于焦磷代谢的治疗策略，在不干扰骨骼矿化的情况下，安全有效地预防人类心血管钙化。这项建议将使用我们开发的体外组织模型和体内遗传小鼠模型来进一步阐明细胞外焦磷酸盐的代谢，并根据焦磷酸盐代谢的不同步骤的影响或基于与焦磷酸盐的化学相似性来筛选原型化合物。在培养的血管和骨组织中进行化学分析和体外分析后，将确定在不抑制骨形成的情况下预测体内疗效的生化参数。然后，化合物将在尿毒症大鼠病理性血管钙化的动物模型中进行测试。该项目将为开发新型血管和瓣膜钙化治疗抑制剂提供一个框架，以改善心血管疾病的治疗和预防。

 DESCRIPTION (provided by applicant): Calcification of blood vessels and heart valves is a serious problem for which there is no specific therapy. Our research has shown that extracellular pyrophosphate is a key endogenous inhibitor of calcification that may be deficient in conditions associated with vascular calcification and can prevent it. However, neither the metabolism nor therapeutic potential of extracellular pyrophosphate is completely understood. The long-term goal of this research is to develop therapeutic strategies based on pyrophosphate metabolism that can safely and effectively prevent cardiovascular calcification in humans without interfering with skeletal mineralization. This proposal will use ex vivo tissue models and in vivo genetic mouse models we have developed to further elucidate the metabolism of extracellular pyrophosphate and to screen prototype compounds selected on the basis of effects on different steps in pyrophosphate metabolism or on the basis of chemical similarity to pyrophosphate. Chemical assays followed by in vitro assays in cultured blood vessels and bone tissue will identify biochemical parameters that predict efficacy in vivo without inhibition of bon formation. Compounds will then be tested in an animal model of pathologic vascular calcification in uremic rats. This project will provide a framework for the development of novel therapeutic inhibitors of vascular and valvular calcification that could improve the treatment and prevention of cardiovascular disease.