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: 8535817
• 负责人: DWIGHT A. TOWLER
• 金额: $ 46.41万
• 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/8535817
• 关键词: Aging; Aorta; Aortic Segment; Aortic Valve Stenosis; Apolipoproteins; Arteriosclerosis; Blood Vessels; Boston; Calcified; Calcium; Cardiac; Central obesity; Clinical Research; Congestive Heart Failure; Coronary; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Dose; Endocrine; Engineering; Fatty acid glycerol esters; Fibrosis; Future; G-Protein-Coupled Receptors; Gene Expression; Genetic; Genotype; Health; Heart Valves; High Density Lipoproteins; Hormones; Human; Hyperglycemia; Hypertension; Hypertriglyceridemia; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intervention; Kidney; Kidney Failure; Low-Density Lipoproteins; Mediating; Medical; Metabolic; Metabolic syndrome; Modeling; Mus; Myofibroblast; Non-Insulin-Dependent Diabetes Mellitus; Osteoblasts; Osteogenesis; Oxidative Stress; Parathyroid Hormone Receptor; Parathyroid gland; Peripheral; Pharmacotherapy; Play; Prevalence; Process; Proteins; Publishing; Receptor Signaling; Regulation; Risk; Risk Factors; Role; Sclerosis; Signal Transduction; Site; Skeleton; Stroke; Structure; Study models; Technology; Teriparatide; Testing; Therapeutic; Tissues; Transgenes; Variant; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; abstracting; aortic valve; aortic valve disorder; base; bone; burden of illness; calcification; calcium metabolism; diabetic; diabetic patient; disorder risk; epidemiologic data; feeding; genetic analysis; improved; interstitial; male; mimetics; osteogenic; osteoprogenitor cell; paracrine; parathyroid hormone (1-34); parathyroid hormone-related protein; postnatal; prevent; programs; receptor; response; skeletal; sudden cardiac death

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，这些变异逐渐损害瓣膜功能，最终增加充血性心力衰竭、卒中和心源性猝死的风险。单纯以他汀类药物为基础的干预治疗策略在治疗钙化性主动脉瓣疾病（CAVD）方面无效。I型糖尿病（T2 DM）和代谢综合征是CAVD风险的主要贡献者。生物化学上，骨软骨细胞基因表达程序由糖尿病患者的钙化瓣膜和血管详细阐述，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-调节骨骼与血管成骨过程，促进前者，但抑制后者在患有钙化性血管病变和动脉纤维化的饮食诱导的T2 DM小鼠模型。对PTH如何调节主动脉瓣硬化的基本理解将指导预防和治疗CAVD的新策略的开发。具体目标是：目标1：“以糖尿病SM 22- Cre; PTH 1 R（fl/fl）;LDLR-/-为研究模型，建立瓣膜肌成纤维细胞PTH/PTHrP受体张力在主动脉瓣硬化发生和进展中的作用。“PTH和PTHrP都通过PTH/PTHrP受体（PTH 1 R）发出信号，PTH 1 R是一种在骨骼、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PTH 1 R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技术来去除主动脉瓣肌成纤维细胞中的PTH 1 R表达，分析SM 22-Cre; PTH 1 R（fl/fl）;我们与合作者Kronenberg博士生成的LDLR-/-小鼠。目标二：“在LDLR-/-; ApoB 100/100小鼠中，检查间歇性PTH（1-34）给药作为限制钙化性主动脉瓣狭窄的内分泌策略的治疗潜力。“我们将研究PTH（1-34）药物治疗对这种具有血液动力学意义的CAS小鼠模型中CAVD的影响。目标三：使用糖尿病Osx-tTA、tetO-CreGFP; PTH 1 R（fl/fl）;LDLR-/-小鼠，确定骨骼成骨细胞PTH 1 R在主动脉瓣和血管硬化的起始和进展中的作用。“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。我们通过消除出生后成骨细胞PTH 1 R在LDLR-/-小鼠中的表达来评估骨骼PTH 1 R信号在新兴的“骨-血管”内分泌轴中的作用。 (End摘要）