GENETICS OF ATRIAL NATRIURETIC FACTOR AND HYPERTENSION

心钠素(ANF)是一种新近发现的多肽，储存在 心房肌细胞内具有强大的利钠和 血管松弛特性。尽管在以下方面取得了相当大的进展 阐明其一级结构并对其进行分离鉴定 基因，ANF作为体液因子在维持性疾病中的意义 心血管动态平衡，特别是与容量和血液有关的 压力控制，几乎是未知的。这是这次活动的主要目的。 定义这一角色的建议。这种方法是多学科的，并将 利用分子生物学、免疫化学和生物化学等领域的方法 生理学。转录和翻译控制机制将是 利用CDNA探针和免疫沉淀程序进行研究 定量测定培养的心房肌细胞对心钠素的反应 特定的刺激。将开发免疫化学技术来测量 并测定血浆中心钠素水平及储存、分泌的结构 和流传形式。完整的动物研究，特别是有意识的 仪器狗，将使我们能够联系心钠素合成的变化(即 转录和翻译调控)并发布到特定的 生理操作，包括肾周炎症的发展 高血压，以及定义神经、血管和体液因素 来规范这些过程。同样，人类的研究也将是 启动以确定ANF在维持容量和压力方面的作用 动态平衡。这些研究也将成为确定 可能代表基因异常的潜在疾病 ANF生产的监管。特别是，限制的方法 片段长度分析用于确定ANF基因或ITS的多态 将利用邻近地区来确定与特定目标的潜在联系 可以预测到这种异常的疾病状态，例如 巴特和戈登综合征。这些技术也将得到推广 为了检验ANF表达的遗传异常可能是 与某些形式的高血压的病因学有关。

Atrial natriuretic factor (ANF) is a recently discovered peptide stored in specific granules within the atrial myocyte that has potent natriuretic and vasorelaxant properties. Although considerable progress has been made in elucidating its primary structure and in isolating and characterizing its gene, the significance of ANF as a humoral factor in maintaining cardiovascular homeostasis, particularly in relation to volume and blood pressure control, is virtually unknown. It is the major aim of this proposal to define this role. The approach is multidisciplinary and will utilize methods from the fields of molecular biology, immunochemistry and phsyiology. Transcriptional and translational control mechanisms will be investigated utilizing CDNA probes and immunoprecipitation procedures to quantitate ANF production in cultured atrial cardiocytes in response to specific stimuli. Immunochemical techniques will be developed to measure ANF levels in plasma and to determine the structure of the stored, secreted and circulating forms. Intact animal studies, in particular the conscious instrumented dog, will allow us to relate changes in ANF synthesis (i.e. transcriptional and translational regulation) and release to specific physiological manipulations, including the development of perinephritic hypertension, as well as to define the neural, vascular and humoral factors that regulate these processes. Similarly, stu7dies in humans will be initiated to define the role of ANF in maintaining volume and pressure homeostasis. These studies will also form the basis for identifying potential diseases that ;may represent abnormalities in the genetic regulation of ANF production. In particular, the method of restriction fragment length analysis to define polymorphisms in the ANF gene or in its vicinity will be utilized to identify potential linkage with particular disease states where such an abnormality might be predicted, such as Bartter's and Gordon's syndromes. These techniques will also be extended to test the hypothesis that a genetic abnormality in ANF expression may be involved in the etiology of certain forms of hypertension.