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Mechanisms of vascular and valvular calcification

血管和瓣膜钙化的机制

基本信息

批准号：
10548126
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-12-31
项目状态：
已结题

项目摘要

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），磷酸钙盐在血管中的不适当沉积，心脏瓣膜和脉管系统，随着年龄的增长，某些遗传疾病，瓣膜疾病、冠状动脉疾病、糖尿病和慢性肾病。钙化这些通常柔顺的器官导致增加的硬度和/或破裂的倾向，对血液动力学和心血管功能有严重影响。尽管公认的血管和瓣膜中血管钙积累的有害作用，目前还没有可用于直接预防或治疗VC的药物疗法。过去 20年来，Giachelli博士的实验室已经领导了一系列研究，导致了一种范式转变的观点，即VC 是一个遗传调节和细胞介导的过程，因此可能适合治疗这些研究揭示了主要的遗传途径、细胞类型和细胞毒性。控制风险投资启动和促进的过程。前进，挑战是了解在各种疾病中，环境，以及可能针对的关键机制途径和/或缺陷治疗目的。因此，拟议的研究重点是了解 1）血管和瓣膜细胞经历成骨细胞和软骨细胞样分化，2）磷酸盐和磷酸盐转运蛋白调节VC，抗钙化机制的失效是VC的原因之一。拟议的研究是一项扩展我们以前和目前的工作，旨在确定生物标志物，治疗，靶点和疗法来治疗这种衰弱的过程。