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Prevention of Vascular Calcification In Chronic Kidney Disease

慢性肾脏病血管钙化的预防

基本信息

批准号：
9009771
负责人：
W CHARLES O'NEILL
金额：
$ 45.15万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9009771
关键词：
Alkaline Phosphatase Animal Genetics Animal Model Aorta Arteries Biochemical Biological Assay Blood Vessels Blood specimen Bone Tissue Cardiovascular Diseases Cardiovascular system Cells Chemicals Chronic Kidney Failure Collaborations Data Development Diphosphates Functional disorder Future Genetic Genetic Models Goals Heart Valves Human Hydrolysis In Vitro Kidney Failure Lesion Liver Metabolism Modeling Nucleotides Osteogenesis Pathologic Patients Perfusion Physiology Play Prevention Production Rattus Recording of previous events Regulation Research Research Personnel Resistance Role Smooth Muscle Myocytes Source Testing Therapeutic Tissue Model Tissues Tooth structure Uremia Vascular Smooth Muscle Vascular calcification analog base bisphosphonate bone bone metabolism calcification calcification inhibitor cardiovascular disorder prevention cardiovascular health experience extracellular falls improved in vitro Assay in vivo in vivo Model inhibitor/antagonist mineralization mortality mouse model novel therapeutic intervention novel therapeutics osteogenic overexpression phosphatase inhibitor phosphoric diester hydrolase prevent prototype public health relevance screening skeletal therapeutic target

项目摘要

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.

描述（由申请人提供）：血管和心脏瓣膜钙化是一个严重的问题，没有特定的治疗方法。我们的研究表明，细胞外焦磷酸盐是一种关键的内源性钙化抑制剂，可能缺乏与血管钙化相关的条件，并可以防止它。然而，无论是代谢还是治疗潜力的细胞外焦磷酸盐是完全理解。这项研究的长期目标是开发基于焦磷酸盐代谢的治疗策略，可以安全有效地预防人类心血管钙化，而不干扰骨骼矿化。该提案将使用我们开发的离体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，并筛选基于对焦磷酸盐代谢中不同步骤的影响或基于与焦磷酸盐的化学相似性选择的原型化合物。在培养的血管和骨组织中进行化学测定，然后进行体外测定，将确定预测体内疗效而不抑制骨形成的生化参数。然后将在尿毒症大鼠的病理性血管钙化的动物模型中测试化合物。该项目将为开发新型血管和瓣膜钙化治疗抑制剂提供框架，从而改善心血管疾病的治疗和预防。