DEVELOPMENTAL REGULATION OF THE B1 ADRENERGIC RECEPTOR GENE

β肾上腺素能受体（β AR）是G蛋白偶联的成员， 受体家族，其包括多种 神经递质和激素。 由于其在以下方面的关键作用， 生理功能，如心肌收缩力，β AR 反应受到严格控制。 众所周知，β AR 是由皮质类固醇和甲状腺激素调节的。 大多数这些 研究是在组织培养或成年动物模型中进行的， 都是在β 2肾上腺素能受体上进行的。 相比之下， 很少或没有关于β 1 AR受体或发育中的胎儿动物的研究。 我们 已经表明糖皮质激素和甲状腺激素都不会增加 β 1 AR在胎仔动物中增加，而在给药动物中增加 出生后 因此，糖皮质激素对β 1 AR的调节， 胎儿的甲状腺激素与成人不同。 这 β 1 AR反应性转换可能代表了一种独特形式 发育调控转录 我们假设 发育中β 1 AR基因表达的转录调控 与成年动物相比， 干扰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β 1 AR 基因和5'侧翼区。 启动子的进行性缺失 已被制造并用于糖皮质激素的鉴定， 甲状腺激素反应元件（GRE和TRE）。 我们已经确定了一 5'侧翼区内的区域，其赋予糖皮质激素 反应以及基础转录的抑制。 当前 该提案旨在（1）确定这些元素在胎儿发育中的作用 成熟，（2）鉴定和克隆转录因子， 负责这种独特的转录调控形式。 这些 这将是首次报道的绘制β 1 AR基因启动子的研究 并将对理解 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.