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
基本信息
- 批准号:8597586
- 负责人:
- 金额:$ 32.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:
项目摘要
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):
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DWIGHT A. TOWLER其他文献
DWIGHT A. TOWLER的其他文献
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{{ truncateString('DWIGHT A. TOWLER', 18)}}的其他基金
Cdc42bpg signaling in arteriosclerosis and vascular fibrosis
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- 批准号:
10448070 - 财政年份:2022
- 资助金额:
$ 32.84万 - 项目类别:
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德克萨斯大学西南分校 - 促进住院医师研究 (UT-StARR) 计划
- 批准号:
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$ 32.84万 - 项目类别:
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:
8856647 - 财政年份:2012
- 资助金额:
$ 32.84万 - 项目类别:
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 - 财政年份:2012
- 资助金额:
$ 32.84万 - 项目类别:
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:
8697129 - 财政年份:2012
- 资助金额:
$ 32.84万 - 项目类别:
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:
8352879 - 财政年份:2012
- 资助金额:
$ 32.84万 - 项目类别:
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