Regulation of ANP Receptor Activity in Vascular Cells

血管细胞中 ANP 受体活性的调节

• 批准号: 6623632
• 负责人: David G Gardner
• 金额: $ 30.25万
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623632
• 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）：利尿钠肽起着 在心血管和肾脏稳态调节中发挥重要作用。他们 以高亲和力与靶细胞上存在的表面受体结合 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增加 钠和水。利尿钠肽受体共有三种：NPR-A、-B 和 -C。 NPR-A 与两种心脏激素、心房肽和脑钠尿肽结合 （分别为 ANP 和 BNP），而 NPR-B 主要与 C型利钠肽（CNP）是在神经系统中产生的， 生殖道和内皮。 NPR-C，即所谓的清除受体，是 在多种组织中表达。虽然它可能拥有独立的 信号活动，它主要负责将 NPs 与 细胞外空间。虽然存在大量关于 与这些受体相关的信号转导活性 每个在整个动物中发挥的生理作用，信息很少 关于它们的调节，特别是在转录方面是可用的 等级。我们之前已经证明 NPR-A 基因的表达是受控的 由该基因的近端启动子中的三个 Sp1 位点和一个 NF-Y 位点组成 基因。我们还表明该基因被受体配体下调 ANP 并通过细胞外张力的增加和一些 核受体配体，包括维生素 D 和视黄酸。在现在 应用程序中，我们将尝试确定转录调控 控制人类 NPR-B 基因表达的控制。两者均为顺式作用 调节元件和与其相关的反式作用蛋白将 进行详细探讨。我们已经克隆并测序了大约 6 kb 该基因的 5'-侧翼序列作为这些研究的前奏。我们也会 研究抑制 NPR-B 和 NPR-C 基因的机制 糖皮质激素的表达和 1,25-二羟基维生素对 NPR-A 的激活 D 和相关靶细胞或整个动物模型中的细胞外张力。 总的来说，这些研究应该定义转录调控 详细控制这些重要基因，并显着增加我们的 了解它们各自在维护心血管方面的作用 和肾脏稳态。