Endocrine Regulation of Calcific Aortic Valve Sclerosis: PTH/PTHRP Receptor Signa

钙化性主动脉瓣硬化的内分泌调节：PTH/PTHRP 受体信号

• 批准号: 8597586
• 负责人: DWIGHT A. TOWLER
• 金额: $ 32.84万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-23 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597586
• 关键词: Endocrine; Regulation; Calcific; Aortic; Valve

DESCRIPTION (provided by applicant): Calcific aortic stenosis (CAS) arises from arteriosclerotic processes and valve morphological variants that progressively impair valve function, ultimately increasing the risk for congestive heart failure, stroke, and sudden cardiac death. Therapeutic strategies focused solely on statin-based intervention have been ineffective in treating calcific aortic valve disease (CAVD). Type I diabetes (T2DM) and metabolic syndrome are major contributors to CAVD risk. Biochemically, osteochondrocytic gene expression programs are elaborated by the calcifying valves and vessels of diabetic patients, indicating that active osteogenic processes contribute to vascular calcium accrual. Our data indicate that parathyroid hormone (PTH) -- the prototypic bone anabolic hormone and master endocrine regulator of vertebrate calcium metabolism -- reciprocally regulates skeletal vs. vascular osteogenic processes, promoting the former but inhibiting the latter in a murine model of diet-induced T2DM afflicted with calcific vasculopathy and arterial fibrosis. A fundamental understanding of how PTH regulates aortic valve sclerosis will guide the development of new strategies to prevent and treat CAVD. Specific Aims are: Aim 1: "To establish the role of valve myofibroblast PTH/PTHrP receptor tone on the initiation and progression of aortic valve sclerosis, using diabetic SM22- Cre;PTH1R(fl/fl);LDLR-/- as a model for study." PTH and PTHrP both signal through the PTH/PTHrP receptor (PTH1R), a G-protein coupled receptor expressed in bone, vascular smooth muscle and valve myofibroblasts, kidney, and other tissues. We assess whether valve myofibroblast PTH1R signaling impacts valve calcification and fibrosis in LDLR-/- mice. We implement Cre-lox technology to remove PTH1R expression from aortic valve myofibroblasts, analyzing the SM22-Cre; PTH1R(fl/fl);LDLR-/- mice we've generated with our collaborator, Dr. Kronenberg. Aim 2: "To examine the therapeutic potential of intermittent PTH(1-34) dosing as an endocrine strategy to limit calcific aortic stenosis in LDLR-/-;ApoB100/100 mice." We wil study the impact of PTH(1-34) pharmacotherapy on CAVD in this hemodynamically-significant murine model of CAS. Aim 3: "To determine the contributions of skeletal osteoblast PTH1R in the initiation and progression of aortic valve and vascular sclerosis, using diabetic Osx- tTA,tetO-CreGFP;PTH1R(fl/fl);LDLR-/- mice." We hypothesize that circulating endocrine or cellular signals elicited by anabolic PTH actions in the skeleton may contribute to reductions in CAVD risk. We assess the role of skeletal PTH1R signaling in the emerging "bone-vascular" endocrine axis by abrogating postnatal osteoblast PTH1R expression in LDLR-/- mice. (End of Abstract)

描述（由申请人提供）： 钙化性主动脉瓣狭窄（CAS）由动脉硬化过程和瓣膜形态变异引起，逐渐损害瓣膜功能，最终增加充血性心力衰竭、中风和心源性猝死的风险。仅仅注重以他汀类药物为基础的干预的治疗策略对于治疗钙化性主动脉瓣疾病（CAVD）是无效的。 I 型糖尿病 (T2DM) 和代谢综合征是 CAVD 风险的主要原因。从生物化学角度来看，骨软骨细胞基因表达程序是由糖尿病患者的钙化瓣膜和血管精心设计的，表明活跃的成骨过程有助于血管钙累积。我们的数据表明，甲状旁腺激素（PTH）——原型骨合成代谢激素和脊椎动物钙代谢的主要内分泌调节剂——相互调节骨骼与血管成骨过程，在患有钙化性血管病和动脉纤维化的饮食诱导T2DM小鼠模型中促进前者但抑制后者。对 PTH 如何调节主动脉瓣硬化的基本了解将指导开发预防和治疗 CAVD 的新策略。具体目标是： 目标 1：“使用糖尿病 SM22-Cre;PTH1R(fl/fl);LDLR-/- 作为研究模型，确定瓣膜肌成纤维细胞 PTH/PTHrP 受体张力在主动脉瓣硬化的发生和进展中的作用。” PTH 和 PTHrP 均通过 PTH/PTHrP 受体 (PTH1R) 发出信号，PTH1R 是一种在骨、血管平滑肌和瓣膜肌成纤维细胞、肾脏和其他组织中表达的 G 蛋白偶联受体。我们评估瓣膜肌成纤维细胞 PTH1R 信号传导是否影响 LDLR-/- 小鼠的瓣膜钙化和纤维化。我们采用Cre-lox技术去除主动脉瓣肌成纤维细胞中PTH1R的表达，分析SM22-Cre； PTH1R(fl/fl)；LDLR-/- 小鼠是我们与合作者 Kronenberg 博士共同培育的。目标 2：“检查间歇性 PTH(1-34) 给药作为内分泌策略限制 LDLR-/-;ApoB100/100 小鼠钙化性主动脉瓣狭窄的治疗潜力。”我们将在这种血流动力学显着的 CAS 小鼠模型中研究 PTH(1-34) 药物治疗对 CAVD 的影响。目标 3：“使用糖尿病 Osx-tTA、tetO-CreGFP；PTH1R(fl/fl)；LDLR-/- 小鼠确定骨骼成骨细胞 PTH1R 在主动脉瓣和血管硬化的发生和进展中的作用。”我们假设骨骼中合成代谢 PTH 作用引起的循环内分泌或细胞信号可能有助于降低 CAVD 风险。我们通过消除 LDLR-/- 小鼠出生后成骨细胞 PTH1R 的表达来评估骨骼 PTH1R 信号在新兴的“骨血管”内分泌轴中的作用。 （摘要完）