ANGIOTENSIN REGULATION OF GENE EXPRESSION

描述：（改编自应用程序）Ang II的慢性刺激 受体影响细胞的增殖、生长和存活， 心血管、神经、内分泌和肾脏组织。 分子 血管紧张素II进入细胞生长遗传程序的机制 和增殖是未知的。 他们的解释，必不可少的 了解AII在神经， 内分泌和心血管系统，是这项建议的中心目标。 首席研究员（PI）的研究揭示了一种新的信号 激活细胞生长和神经、神经胶质和 平滑肌谱系。 这一途径是通过诱导 成纤维细胞生长因子（FGF-2）和FGF受体-1（FGFR-1）基因， 随后FGF-2和FGFR-1蛋白直接积累到细胞中 原子核 核FGF-2和FGFR-1通过前馈机制激活 转录其他基因并诱导细胞生长和进入细胞 周期 PI已经表明，这种新的细胞核内FGF-2/FGFR-1 途径被肾上腺髓质细胞中的Ang II受体激活， 星形胶质细胞和平滑肌细胞。 通过分子机制 Ang II激活FGF-2-FGFR-1通路的初始步骤是研究的重点。 这个提议。 PI表明，Ang II通过激活FGF-2基因， 诱导具有Ang II反应区（Ang）的多蛋白复合物 IIRR，-555/-512 BP）的FGF-2启动子，该启动子也介导FGF-2基因 通过可溶性细胞因子活化和减少细胞接触。 AngIIRR是 与cAMP/PKC应答序列（-625/-556 BP）分离，含有独特的 蛋白结合序列，并与新的转录因子相互作用。 PI的研究结果还表明，FGF-2和FGFR-1蛋白 在细胞核中积累，刺激与血管紧张素IIRR相关的 反式激活复合物，从而增强血管紧张素II激活， FGF-2基因。 因此，根据所有这些信息，本报告的中心目标是 本研究旨在通过血管紧张素II的表达来探讨核转导机制 激活FGF-2基因和介导该过程的Ang II受体类型 activation. 作为模型，PI将使用培养的非转化牛 肾上腺髓质细胞（BAMC）。 其目的如下：1）识别 并克隆形成多种蛋白的肾上腺髓质反式作用因子 与Ang IIRR复合物，并确定AT 2和AT 1在激活中的作用 2）进一步确定Ang IIRR的结构 复合物及其克隆蛋白组分的功能，以及3） 确定核FGF-2和FGFR-1蛋白在Ang II激活中的作用 FGF-2启动子和Ang IIRR复合物。

DESCRIPTION: (Adapted from the application) Chronic stimulation of Ang II receptors effects proliferation, growth and survival of cells in cardiovascular, neural, endocrine and kidney tissues. The molecular mechanism by which Ang II accesses genetic programming for the cell growth and proliferation are unknown. Their elucidation, essential for understanding physiological and pathophysiological effects of AII in neural, endocrine and cardiovascular system, is the central goal of this proposal. The principal investigator (PI's) studies have revealed a new signaling mechanism that activates cell growth and proliferation of neural, glial and smooth muscle lineages. This pathway is initiated by an induction of fibroblast growth factors (FGF-2) and FGF receptor-1 (FGFR-1) genes with the consequent accumulation of FGF-2 and FGFR-1 proteins directly into the cell nucleus. Nuclear FGF-2 and FGFR-1 activate through a feed-forward mechanism transcription of other genes and induce cell growth and entry into the cell cycle. The PI has shown that this new intracrine-nuclear FGF-2/FGFR-1 pathway is activated by Ang II receptor in adrenal medullary cells, astrocytes and smooth muscle cells. The molecular mechanisms through which Ang II activates the initial steps in FGF-2-FGFR-1 pathway is the focus of this proposal. The PI indicates that Ang II activates FGF-2 gene by inducing a multiple-protein complex with an Ang II responsive region (Ang IIRR, -555/-512 BP) of FGF-2 promotor that also mediates FGF-2 gene activation by soluble cytokines and reduced cell contact. Ang IIRR is separate from cAMP/PKC responsive sequences (-625/-556 BP), contains unique protein-binding sequences and interacts with new transcriptional factors. The PI's findings also indicate that the FGF-2 and FGFR-1 proteins accumulating in the cell nucleus, stimulate the Ang IIRR-associated transactivating complex and thereby serve to enhance Ang II activation of FGF-2 gene. Thus, based on all of this information, the central aim of this project is to identify nuclear transduction mechanism through with Ang II activates the FGF-2 gene and the type of Ang II receptors that mediate this activation. As a model, the PI will use cultured, non-transformed bovine adrenal medullary cells (BAMC). The aims are as follows: 1) To identify and clone adrenal medullary trans-acting factors that form multiple protein complex with Ang IIRR and to determine the role of AT2 and AT1 in activation of FGF-2 gene promotor, 2)To further determine the structure of Ang IIRR complex and the functions of its cloned protein components, and 3) To determine the role of nuclear FGF-2 and FGFR-1 proteins in Ang II activation of FGF-2 promotor and of Ang IIRR complex.