ANP RECEPTOR GENE--TARGETING AND EXPRESSION

高血压和心血管疾病是严重的健康问题 工业化世界中的许多人。心钠素 心钠素(ANP)是一种内源性的、有效的降压激素，它能诱导 利钠、利尿、血管松弛和抗增殖作用， 血压和心血管控制中的重要因素 动态平衡。监管行动中涉及的主要基因座之一 心钠素的受体是鸟氨酰环化酶连接的心钠素受体，被命名为 AS Npra，其心钠素结合活性和鸟苷酸环化酶活性不同 在不同的组织中有显著的差异。然而，这些的分子基础 NprA基因的活性、功能表达和调控 不是很清楚。进一步理解生物作用(S) 由Npra扮演，Npra的转录调控和功能 基因将使用模型系统细胞系和NprA基因进行研究- 靶向突变小鼠模型的具体目的如下：1) 证明了NprA基因表达的转录调控 确定保守的监管区域。这一具体的重点 目的是测定小鼠NprA的全核苷酸序列 基因，分析结构组织并与大鼠基因进行比较 序列以识别5‘侧翼的顺式调节元件和 通过以下瞬时表达式确定这些元素的功能 培养的细胞。2)生化和生理鉴定 从NprA基因缺失或缺失的后果分析NprA基因的功能(S) 具有0、1、2、3或4个拷贝的基因靶向小鼠的串联复制 Npra基因。这一特定目标的重点是确定 NprA基因剂量和零突变对细胞的影响 体内和体内突变小鼠的发育和生理反应 体外分离这些小鼠的培养细胞。长期的 研究提案的目的是在分子水平上阐明 水平、NprA基因的性质和功能模式在同样多的 尽可能多地提供细节。研究领域的进展将 极大地加强和提高我们对遗传和 评价NprA在控制赤霉病中作用的分子方法 体液量、血压、充血性心力衰竭等 生理机能(S)。由此产生的知识应该产生新的 高血压的治疗靶点及预防 高血压相关的心血管疾病。

Hypertension and cardiovascular disease are serious health problems for many individuals in the industrialized world. Atrial natriuretic peptide (ANP) is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant and antiproliferative effects, important factors in the control of blood pressure and cardiovascular homeostasis. One of the principal loci involved in the regulatory action of ANP is the guanylyl cyclase-linked ANP receptor (GC-A), designated as Npra, whose ANP-binding and guanylyl cyclase activities vary remarkably in different tissues. However, the molecular basis of these activities and the functional expression and regulation of Npra gene are not well understood. To further understand the biological role(s) played by Npra, the transcriptional regulation and function of the Npra gene will be studied using a model system cell line and Npra gene- targeted mutant mouse models in the following specific aims: 1) Demonstrate the transcriptional control of the Npra gene expression by identifying conserved regulatory regions. The focus of this specific aim is to determine the complete nucleotide sequence of murine Npra gene, analyze the structural organization and compare with rat gene sequence to identify the 5'-flanking cis-regulatory elements and determine the function of these elements by transient expression in cultured cells. 2) Identify the biochemical and physiological function(s) of Npra gene by analyzing the consequence of its loss or its tandem duplication in gene-targeted mice having, 0, 1, 2, 3, or 4 copies of the Npra gene. The focus of this specific aim is to determine the impact of the Npra gene-dosage and null mutation on cellular, developmental and physiological responses in mutant mice in vivo and in cultured cells isolated from these mice in vitro. The long-term objective of the research proposal is to elucidate, at the molecular level, the nature and mode of functioning of the Npra gene in as much detail as possible. Progress in the filed of research will significantly strengthen and advance our knowledge of genetic and molecular approaches to evaluate the role of Npra in the control of fluid volume, blood pressure, congestive heart failure and other physiological function(s). The resulting knowledge should yield new therapeutic targets for the treatment of hypertension and prevention of hypertension-related cardiovascular disorders.