GENETICS OF ATRIAL NATRIURETIC FACTOR AND HYPERTENSION

心房钠尿因子和高血压的遗传学

• 批准号: 3349723
• 负责人: ROBERT M GRAHAM
• 金额: $ 40.18万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1990-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3349723
• 关键词: Bartter's syndrome; affinity chromatography; atrial natriuretic peptide; blood chemistry; blood flow measurement; body water; complementary DNA; electrolyte balance; electron microscopy; familial hypertension; genetic manipulation; genetic transcription; genetic translation; heart cell; high performance liquid chromatography; histochemistry /cytochemistry; homeostasis; human subject; hypertension; immunochemistry; immunoprecipitation; linkage mapping; molecular cloning; molecular genetics; monoclonal antibody; peptide chemical synthesis; radioimmunoassay; radiotracer; renal hypertension; saluretic; synthetic peptide; tissue /cell culture

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.

心房利钠因子（ANF）是最近发现的一种肽， 心房肌细胞内的特异性颗粒，具有强效利尿钠， 血管舒张性质。 虽然在以下方面取得了相当大的进展： 阐明其一级结构并分离和表征其 心钠素作为一种体液因子，在维持 心血管稳态，特别是与容量和血液有关的 压力控制几乎是未知的。 这是主要目的， 这是为了明确这个角色。 该方法是多学科的， 利用分子生物学、免疫化学和 生理学 转录和翻译控制机制将是 研究利用cDNA探针和免疫沉淀程序， 在培养的心房心肌细胞中定量ANF的产生， 具体的刺激。 将开发免疫化学技术来测量 血浆中ANF的水平，并确定其结构的储存，分泌 循环的形式。 完整的动物研究，特别是有意识的 仪器狗，将允许我们将ANF合成的变化（即， 转录和翻译调控）和释放到特定的 生理操作，包括肾周炎的发展 高血压，以及确定神经，血管和体液因素 来调节这些过程。 同样，在人类中的研究将是 开始定义ANF在维持容量和压力方面的作用 体内平衡 这些研究也将成为确定 潜在的疾病;可能代表遗传异常 ANF生产的控制。 特别是，限制方法 片段长度分析以确定ANF基因或其 将利用邻近地区来确定与特定 可以预测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 为了验证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。