Regulation of ANP Receptor Activity in Vascular Cells

血管细胞中 ANP 受体活性的调节

基本信息

批准号：
7994145
负责人：
David G Gardner
金额：
$ 38.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-07-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7994145
关键词：
Affect Atrial Natriuretic Factor Atrial Natriuretic Factor Receptors Blood Pressure Blood Vessels Cardiovascular system Cells Dihydroxycholecalciferols Down-Regulation Duct (organ) structure Endocrine Extracellular Domain Family Funding Gene Expression Genes Genetic Transcription Glucocorticoids Guanylate Cyclase Heart Heart Hypertrophy Homeostasis Hormonal In Vitro Indium Kidney Knock-out Ligand Binding Ligands Link Mediating Modeling Molecular Mus Natriuretic Peptides Nuclear Receptors Osmoregulation Particulate Peptides Phosphotransferases Play Regulation Renin-Angiotensin System Role Serum Signal Transduction Smooth Muscle Myocytes System Transmembrane Domain Up-Regulation Vascular Smooth Muscle Vitamin D analog atrial natriuretic factor receptor A extracellular familial hypertension in vivo palliative peptide B receptor skeletal

项目摘要

The natriuretic peptides (NPs) collectively represent a family of hormonal peptides that play important roles in the control of renal, cardiovascular, endocrine and skeletal homeostasis. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BMP)signal predominantly through the type A natriuretic peptide receptor (NPR-A), a single transmembrane domain receptor which links a ligand-binding extracellular domain to a particulate guanylyl cyclase domain at the carboxy terminus of the molecule. Studies carried out during the previous funding period have demonstrated that the transcription of the NPR-A gene (nprl) is controlled by a extracellular tonicity as well as the nuclear receptor ligand 1,25 dihydroxyvitamin D(VD). NPR-A expression in the inner medullary collecting duct is osmotically regulated and a significant portion of this regulation is signaled by the serum and glucocorticoid inducible kinase (sgk) which is itself induced by increased extracellular tonicity. We have identified a candidate element in the sgkl promoterwhich we believe controls its osmoregulation, and inferentially the osmoregulation of this transcriptional cascade. We will attempt to elucidate the molecular details that govern this osmoregulatoryactivity. VD has been shown to possess a variety of palliative effects in the cardiovascular system including reduction in blood pressure and suppression of cardiac hypertrophy. We hypothesize that some portion of the palliative effects of VD in the heart and vasculature may be mediated through upregulation of NPR-A levels and activity. In the present proposalwe will use a combination of in vitro studies in VDR -/- cells, in vivo studies involving murine models of genetic hypertension and knockout of the VDR selectively in vascular smooth muscle and renal collecting duct cells in an attempt to confirm the mechanistic link betweenVD's cardio- and vasculoprotective activity and stimulation of NPR-A expression/activity. Collectively, this proposal should provide us with a detailed understanding of how the NPR-A gene is regulated and the role that this regulation plays in the control of cardiovascular homeostasis.

亚位尿肽（NP）统称为荷尔蒙肽家族，起着重要作用控制肾脏，心血管，内分泌和骨骼稳态。心房亚钠肽（ANP）和B型亚替肽（BMP）信号主要通过A型亚位曲霉受体受体。（NPR-A），一个单个跨膜结构域受体，将配体结合细胞外域连接到A 分子的羧基末端处的颗粒状鸟叶基环酶结构域。在此期间进行的研究以前的资金期表明NPR-A基因（NPRL）的转录受A控制细胞外强度以及核受体配体1,25二羟基维生素D（VD）。内部髓质收集管中的NPR-A表达受到渗透调节，很大一部分该调节由血清和糖皮质激素诱导激酶（SGK）发出信号，这本身是由细胞外强度增加。我们已经确定了SGKL启动子中的候选元素相信控制其渗透调节，并推断该转录级联反应的渗透压。我们将尝试阐明控制这种渗透压的分子细节。 VD已显示在心血管系统中具有多种姑息作用，包括还原在血压和心脏肥大的抑制中。我们假设其中一部分 VD在心脏和脉管系统中的姑息作用可以通过上调NPR-A水平介导和活动。在本提案中，我们将在VDR - / - 细胞中使用体外研究的组合，体内涉及遗传性高血压和VDR的鼠模型在血管中的研究平滑肌和肾脏收集管道细胞，以确认VD之间的机械联系心脏和血管保护活性以及NPR-A表达/活性的刺激。总的来说，这提案应为我们提供对NPR-A基因的调节以及角色的详细了解该法规在控制心血管稳态的控制方面发挥了作用。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy.

DOI：
10.1161/circulationaha.111.032680
发表时间：
2011-10-25
期刊：
Circulation
影响因子：
37.8
作者：
Chen S;Law CS;Grigsby CL;Olsen K;Hong TT;Zhang Y;Yeghiazarians Y;Gardner DG
通讯作者：
Gardner DG

Vitamin D-dependent suppression of endothelin-induced vascular smooth muscle cell proliferation through inhibition of CDK2 activity.

DOI：
10.1016/j.jsbmb.2009.11.002
发表时间：
2010-02-15
期刊：
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
影响因子：
4.1
作者：
Chen, Songcang;Law, Christopher S.;Gardner, David G.
通讯作者：
Gardner, David G.

A murine model of isolated cardiac steatosis leads to cardiomyopathy.

DOI：
10.1161/hypertensionaha.110.160655
发表时间：
2011-02
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
0
作者：
Glenn DJ;Wang F;Nishimoto M;Cruz MC;Uchida Y;Holleran WM;Zhang Y;Yeghiazarians Y;Gardner DG
通讯作者：
Gardner DG

Lipids and the heart: neither feast nor famine.