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）： 钙化主动脉狭窄（CAS）是由动脉粥样硬化过程和瓣膜形态学变异引起的，这些变体逐渐损害了瓣膜功能，最终增加了充血性心力衰竭，中风和突然心脏死亡的风险。仅关注他汀类药物干预的治疗策略在治疗钙化主动脉瓣疾病（CAVD）方面无效。 I型糖尿病（T2DM）和代谢综合征是CAVD风险的主要因素。从生物化学上讲，骨质细胞基因表达程序通过钙化瓣膜和血管详细说明糖尿病患者的血管，表明活性成骨过程有助于血管钙应计。我们的数据表明，甲状旁腺激素（PTH） - 脊椎动物钙代谢的原型骨合成激素和主内分泌调节剂 - 相互调节骨骼与血管成骨造成过程T2DM患有钙化血管病和动脉纤维化。对PTH如何调节主动脉瓣硬化的基本了解将指导预防和治疗CAVD的新策略的发展。具体目的是：目标1：“使用糖尿病SM22-CRE； pth1r（fl/fl），建立瓣膜肌纤维细胞PTH/PTHRP受体音调在主动脉瓣硬化的启动和进展中的作用； ldlr - / - 作为模型进行研究。” PTH和PTHRP均通过PTH/PTHRP受体（PTH1R）发出信号，这是一种在骨，血管平滑肌和瓣膜肌纤维细胞，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。我们实施Cre-Lox技术以从主动脉瓣肌纤维细胞中删除PTH1R表达式，从而分析SM22-CRE； pth1r（fl/fl）; ldlr - / - 小鼠与我们的合作者Kronenberg博士生成。目标2：“检查间歇性PTH（1-34）给药的治疗潜力，作为限制LDLR - / - ; APOB100/100小鼠的钙化主动脉狭窄的内分泌策略。”我们将研究PTH（1-34）药物疗法对CAS的血液动力学鼠模型中CAVD的影响。目标3：“使用糖尿病性OSX-TTA，TETO-CREGFP; pth1r（fl/fl）； ldlr - / - 小鼠。我们假设骨骼中合成代谢的PTH作用引起的循环内分泌或细胞信号可能导致CAVD风险的降低。我们通过废除LDLR - / - 小鼠中骨骼PTH1R信号传导在新出现的“骨血管”内分泌轴上的作用。 （抽象的结尾）