REGULATION OF AT1 AND AT2 RECEPTORS DURING ONTOGENY

AT1 和 AT2 受体在个体发育过程中的调节

• 批准号: 2151885
• 负责人: JEAN E ROBILLARD
• 金额: $ 18.6万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2151885
• 关键词: RNase protection assay; angiotensin II; animal genetic material tag; atomic absorption spectrometry; biological signal transduction; cardiovascular function; developmental genetics; early embryonic stage; embryo /fetus; flame photometry; gestational age; growth /development; in situ hybridization; kidney function; messenger RNA; northern blottings; nucleic acid biosynthesis; protein biosynthesis; protooncogene; radioimmunoassay; receptor expression; scintillation counter; sheep; ultrasound blood flow measurement; urinalysis

Our present understanding of the role of AT1 and AT2 receptors during development comes essentially from studies performed in vitro (1-4). To our knowledge, there have been no studies in vivo that have investigated the physiological role of AT1 or AT2 receptors on cardiovascular and renal functions during fetal development. The differential expression of AT1 and AT2 receptors during kidney development, (see preliminary data) suggest that the physiological role of AII changes during development. Based on these previous studies we are postulating that the physiological renal responses to AT1 and AT2 receptor activation during fetal life are dependent on the developmental changes in the anatomical distribution and levels of expression of AT1 and AT2 receptor and on the maturation of signal transduction mechanisms regulating the cellular responses to AT1 and AT2 receptor activation. To test this hypothesis, the present proposal is designed (a) to elucidate the physiological role and molecular regulation of AT1 and AT2 receptors during fetal life in sheep; (b) to determine the influence of maturational changes in signal transduction mechanisms (cAMP, phospholipase C, cCMP, and phosphotyrosine phosphatase) on the physiological renal responses to AT1 and AT2 receptor activation; and (c) to elucidate both in vivo and in vitro the respective role of AT1 and AT2 receptors on the regulation of proto-oncogenes (c-fos, c-myc, n-myc) and growth related genes (TGF-alpha, TGF-beta, IGF-I and IGF-II) at different times during fetal renal development. These studies will elucidate for the first time the mechanisms regulating the expression and physiological activity of AT1 and AT2 receptors during fetal renal development. Understanding of these mechanisms is essential to determine and to prevent potential fetal harmful effects of these new angiotensin II receptor antagonists when used in pregnant women and in preterm and term newborn infants.

我们目前对 AT1 和 AT2 受体在 开发主要来自体外研究 (1-4)。 据我们所知，尚无体内研究表明 研究了 AT1 或 AT2 受体的生理作用 胎儿发育期间的心血管和肾脏功能。这 AT1和AT2受体在肾脏过程中的差异表达 发育，（见初步数据）表明生理作用 开发过程中 AII 的变化。 基于这些先前的研究，我们 假设肾对 AT1 和 AT2 的生理反应 胎儿时期受体的激活取决于发育 AT1 的解剖分布和表达水平的变化 和AT2受体以及信号转导机制成熟的影响 调节细胞对 AT1 和 AT2 受体激活的反应。 为了检验这一假设，本提案旨在 (a) 阐明 AT1 和 AT2 的生理作用和分子调控 绵羊胎儿时期的受体； (b) 确定影响 信号转导机制（cAMP、 磷脂酶 C、cCMP 和磷酸酪氨酸磷酸酶） AT1 和 AT2 受体激活的肾脏生理反应；和 (c) 阐明AT1在体内和体外各自的作用 和 AT2 受体对原癌基因（c-fos、c-myc、 n-myc）和生长相关基因（TGF-α、TGF-β、IGF-I 和 IGF-II） 胎儿肾脏发育的不同时期。 这些研究将 首次阐明表达调控机制 AT1和AT2受体在胎儿肾病过程中的作用和生理活性 发展。 了解这些机制对于 确定并防止这些新产品对胎儿潜在的有害影响 血管紧张素 II 受体拮抗剂用于孕妇和 早产儿和足月新生儿。