DEVELOPMENTAL REGULATION OF THE B1 ADRENERGIC RECEPTOR GENE

β肾上腺素能受体(BetaAR)是G蛋白偶联的成员 受体家族，包括多种受体 神经递质和荷尔蒙。因为他们在 生理功能，如心肌收缩功能，β-AR 响应性受到严格控制。众所周知，BetaAR 受皮质类固醇和甲状腺激素的调节。其中大多数都是 研究是在组织培养或成年动物模型中进行的，几乎 所有实验都是在β2肾上腺素能受体上完成的。相比之下，有以下几种 很少或根本没有关于Beta1AR受体或发育中的胚胎动物的研究。我们 已经表明糖皮质激素和甲状腺激素都不会增加 胚胎动物中的β-1AR，而接受治疗的动物中有增加 出生后。因此，糖皮质激素对β-AR的调节和 胎儿体内的甲状腺激素与成人的不同。这 切换到Beta1AR响应可能代表一种独特形式 发育调节转录。我们假设独一无二的 β_1AR基因在发育过程中的转录调控 动物与成年动物相比，是由于存在特定的 干扰激素受体和基因的转录因子 互动。为了研究这一机制，我们克隆了绵羊的Beta1AR 基因和5‘侧翼区。启动子的渐进式删除 已制成并正在用于鉴定糖皮质激素和 甲状腺激素反应元件(GRE和Tre)。我们已经确定了一个 5‘侧翼区域内提供糖皮质激素的区域 对基本转录的反应和抑制。海流 建议设计(1)以确定这些元素在胎儿中的作用 成熟，(2)鉴定和克隆转录因子(S) 负责这种独特形式的转录调控。这些 将是首次报道的定位Beta1AR基因启动子的研究 这将对了解糖尿病的病理生理学有重要意义。 所有发育阶段的心血管疾病。

Beta adrenergic receptors (betaAR) are members of the G-protein coupled receptor family which includes receptors for a variety of neurotransmitters and hormones. Because of their critical role in physiological functions such as myocardial contractility, betaAR responsiveness is tightly controlled. It is well established that betaAR are regulated by corticosteroids and thyroid hormones. Most of these studies were done in tissue culture or in adult animal models and nearly all were done on the beta2 adrenergic receptor. In contrast, there are few or no studies on beta1AR receptors or in developing fetal animals. We have shown that neither glucocorticoids nor thyroid hormones increase beta1AR in fetal animals whereas there is an increase in animals treated after birth. Thus, the regulation of beta1AR by glucocorticoids and thyroid hormones in the fetus is distinct from that of adults. This switch in beta1AR responsiveness may represent a unique form of developmentally regulated transcription. We hypothesize that the unique transcriptional regulation of beta1AR gene expression in developing animals compared to adults is due to the presence of specific transcription factors which interfere with the hormone-receptor and gene interaction. To study this mechanism, we have cloned the ovine beta1AR gene and 5' flanking region. Progressive deletions of the promoter have been made and are being used for identification of glucocorticoid and thyroid hormone response elements (GRE and TRE). We have identified a region within the 5' flanking region which confers glucocorticoid responsiveness as well as repression of basal transcription. The current proposal is designed (1) to determine the role of these elements in fetal maturation, (2) to identify and clone the transcription factor(s) responsible for this unique form of transcriptional regulation. These will be the first reported studies to map the promoter of the beta1AR gene and will be of importance in understanding the pathophysiology of cardiovascular diseases at all developmental stages.