Regulation of ANP Receptor Activity in Vascular Cells

血管细胞中 ANP 受体活性的调节

• 批准号: 6852638
• 负责人: David G Gardner
• 金额: $ 30.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6852638
• 关键词: 1,25 dihydroxycholecalciferol; atrial natriuretic peptide; body fluid osmolarity; cardiovascular function; gene expression; genetic regulatory element; genetic transcription; guanylate cyclase; hormone regulation /control mechanism; in situ hybridization; laboratory mouse; laboratory rat; neuropeptide receptor; nuclear receptors; posttranslational modifications; protein structure function; receptor binding; receptor expression; renal tubular transport; retinoid binding proteins; tissue /cell culture; transcription factor; transfection; vascular smooth muscle; vitamin D receptors

DESCRIPTION (provided by the applicant): The natriuretic peptides play an important role in the regulation of cardiovascular and renal homeostasis. They bind with high affinity to surface receptors present on target cells and initiate a series of signal transduction events that, in the whole animal, result in reductions in blood pressure and an increase in renal excretion of sodium and water. There are three natriuretic peptide receptors, NPR-A, -B and -C. NPR-A binds to two cardiac hormones, atrial and brain natriuretic peptide (ANP and BNP, respectively) while NPR-B associates predominantly with the C-type natriuretic peptide (CNP) which is produced in the nervous system, reproductive tract and endothelium. NPR-C, the so-called clearance receptor, is expressed in a wide variety of tissues. While it may possess independent signaling activity, it is primarily responsible for sequestering NPs from the extracellular space. While a large body of information exists regarding the signal transduction activity associated with these receptors and the physiological role that each plays in the whole animal, very little information is available regarding their regulation, particularly at a transcriptional level. We have shown previously that expression of the NPR-A gene is controlled by three Sp1 sites and a single NF-Y site in the proximal promoter of that gene. We have also shown that the gene is down regulated by the receptor ligand ANP and upregulated by increases in extracellular tonicity and a number of nuclear receptor ligands, including vitamin D and retinoic acid. In the present application, we will attempt to determine the transcriptional regulatory controls that govern expression of the human NPR-B gene. Both the cis-acting regulatory elements and the trans-acting proteins that associate with them will be explored in detail. We have cloned and sequenced approximately 6 kb of 5'-flanking sequence from this gene as a prelude to these studies. We will also investigate the mechanism(s) underlying suppression of NPR-B and NPR-C gene expression by glucocorticoids and activation of NPR-A by 1,25-dihydroxyvitamin D and extracellular tonicity in relevant target cell or whole animal models. Collectively, these studies should define the transcriptional regulatory control of these important genes in detail and add significantly to our understanding of their respective roles in the maintenance of cardiovascular and renal homeostasis.

描述（由申请人提供）：Natriutet肽发挥 在心血管和肾稳态调节中的重要作用。他们 与靶细胞上存在的表面受体高亲和力结合， 启动一系列信号转导事件，在整个动物中， 导致血压降低和肾脏排泄的增加 钠和水。有三种亚钠肽受体，NPR -A，-b和 -c。 NPR-A与两种心脏激素结合，心房和脑纳替肽 （分别为ANP和BNP）NPR-B主要与 神经系统中产生的C型亚钠肽（CNP）， 生殖道和内皮。 NPR-C是所谓的清除受体，是 在各种组织中表达。虽然它可能具有独立 信号活性，它主要负责隔离NP 细胞外空间。虽然存在有关该信息的大量信息 与这些受体相关的信号转导活性和 每个动物中每个动物中扮演的生理角色，很少的信息 有关其法规的可用，尤其是在转录中 等级。我们先前已经证明了NPR-A基因的表达受到控制 在近端启动子中通过三个SP1站点和一个NF-Y站点 基因。我们还表明该基因被受体配体调节 ANP并被细胞外强度增加和许多 核受体配体，包括维生素D和视黄酸。现在 应用，我们将尝试确定转录调节 控制控制人NPR-B基因表达的。顺式作用 调节元素及其相关的跨作用蛋白将 详细探讨。我们已经克隆并测序了约6 kb的 该基因的5'频序序列是这些研究的前奏。我们也会 研究NPR-B和NPR-C基因的基本抑制机制 糖皮质激素表达和NPR-A激活1,25-二羟基维生素 相关靶细胞或整个动物模型中的D和细胞外强度。 总的来说，这些研究应定义转录调节性 详细控制这些重要基因，并显着增加 了解他们在维持心血管中的各自角色 和肾稳态。