Mechanisms of vascular and valvular calcification

血管和瓣膜钙化的机制

• 批准号: 10321921
• 负责人: Cecilia M Giachelli
• 金额: $ 93.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321921
• 关键词: Aging; Biological Markers; Blood Vessels; Calcium; Cardiovascular Physiology; Cell physiology; Cells; Chondrocytes; Chronic Kidney Failure; Clinical Research; Coronary Arteriosclerosis; Deposition; Diabetes Mellitus; Disease; Foundations; Future; Genetic; Genetic Diseases; Heart Valves; Inorganic Phosphate Transporter; Mediating; Organ; Osteoblasts; Pathway interactions; Pharmacotherapy; Process; Rupture; Salts; Therapeutic; Vascular calcification; Work; calcification; calcium phosphate; cardiac vasculature; cell type; hemodynamics; prevent; targeted treatment; therapeutic target; translational study

Vascular calcification (VC), the inappropriate deposition of calcium phosphate salts in cardiac valve and vasculature, is increased with aging, certain genetic disorders, valve disease, coronary artery disease, diabetes and chronic kidney disease. Calcification of these normally compliant organs leads to increased stiffness and/or tendency to rupture, and has severe impacts on hemodynamics and cardiovascular function. Despite the recognized deleterious effects of vascular calcium accrual in blood vessels and valves, there are currently no drug therapies available to directly prevent or treat VC. In the past 20 years, Dr. Giachelli's lab has led studies leading to the paradigm-shifting view that VC is a genetically regulated and cell-mediated process, and thus potentially amenable to treatment. These studies have revealed major genetic pathways, cell types and cellular processes that control the initiation and promotion of VC. Moving forward, the challenge is to understand which of these processes is most important under various disease settings, and key mechanistic pathways and/or deficiencies that might be targeted for therapeutic purposes. Thus, the proposed studies focus on understanding the mechanisms by which 1) vascular and valvular cells undergo osteoblast and chondrocyte-like differentiation, 2) phosphate and phosphate transporters regulate VC, and 3) failed anticalcific mechanisms contribute to VC. The proposed studies are an extension of our previous and current work that aim to identify biomarkers, therapeutic targets and therapies to treat this debilitating process.

血管钙化(VC)，钙磷盐在血管内的不适当沉积 心脏瓣膜和血管系统，是随着年龄的增长，某些遗传性疾病，瓣膜 疾病、冠状动脉疾病、糖尿病和慢性肾脏疾病。骨钙化 这些正常顺应的器官会导致僵硬和/或破裂倾向的增加， 对血流动力学和心血管功能有严重影响。尽管 认识到血管和瓣膜中血管钙积聚的有害影响， 目前还没有直接预防或治疗VC的药物疗法。在过去 20年来，贾切利博士的实验室领导的研究导致了一种范式转变的观点，即风投 是一个受基因调控和细胞介导的过程，因此有可能服从于 治疗。这些研究揭示了主要的遗传途径、细胞类型和细胞 控制风险投资的发起和推广的流程。展望未来，挑战 就是了解这些过程中的哪一个在各种疾病下是最重要的 环境，以及可能针对的关键机械途径和/或缺陷 治疗目的。因此，拟议的研究侧重于了解 1)血管和瓣膜细胞通过成骨细胞和 软骨细胞样分化，2)磷酸和磷酸转运蛋白调节VC， (3)抗钙机制失效是VC的致病因素。建议的研究是 扩展我们以前和现在的工作，目的是识别生物标记物，治疗性 治疗这一衰弱过程的靶点和疗法。