Transcriptional regulation of H. pylori-mediated gastric inflammation and cancer

描述(申请人提供)：幽门螺杆菌感染会导致慢性胃炎和消化性溃疡，是导致胃癌的最大危险因素。幽门螺杆菌的发病机制被认为与感染引发的慢性胃炎有关，慢性胃炎的特征是许多炎症基因的表达增强。转录因子核因子？B通过调节这些炎症基因的表达，在幽门螺杆菌引起的炎症反应和胃炎中发挥关键作用。最近的研究包括我们的研究表明，由CDK9和Cyclin T1组成的通用转录延伸因子P-TEFb(正转录延伸因子b)对于依赖于NF-B的炎症基因的表达是必不可少的。P-TEFb的活性在细胞内受到严格的调控，它与HEXIM1和7SK SnRNA或Brd4的结合。HEXIM1和Brd4也参与了核因子B介导的炎症基因表达和肿瘤形成，是药物开发的潜在靶点。本研究的总体目标是研究这些转录调控因子在幽门螺杆菌介导的炎症反应中的调节和功能，并探索这些调控因子在预防和治疗幽门螺杆菌引发的胃病中的治疗潜力。在具体目标1中，我们将在培养细胞和动物体内研究Brd4在幽门螺杆菌诱导的胃病中的重要作用，包括蒙古沙土鼠和胃上皮细胞特异性Brd4条件基因敲除小鼠。我们还将探索Brd4抑制剂JQ1作为预防和治疗幽门螺杆菌诱导的炎症性疾病和胃癌的药物的潜力。在特定的目标2中，我们将剖析HEXIM1在核因子-βB失活中的作用 以及幽门螺杆菌引起的炎症反应和胃癌。我们还将研究使用HMBA干预幽门螺杆菌诱导的炎症反应和胃癌发生的可能性。在特定的目标3中，我们将确定CDK9的激活是如何被调节的，以有效地转录幽门螺杆菌诱导的炎症基因。我们还将评估CDK9抑制剂黄烷醇对幽门螺杆菌引起的胃病的治疗潜力。

DESCRIPTION (provided by applicant): H. pylori infection causes chronic gastritis and peptic ulceration and is the strongest risk factor for the development of gastric cancer. The pathogenesis of H. pylori is believed to be associated with infection-initiated chronic gastritis, which is characterized by enhanced expression of many inflammatory genes. The transcription factor NF-?B plays a key role in H. pylori-initiated inflammatory response and gastritis by regulating the expression of these inflammatory genes. Recent studies including ours have shown that the general transcriptional elongation factor P-TEFb (the positive transcription elongation factor b), comprised of CDK9 and Cyclin T1, is essential for the expression of NF-?B-dependent inflammatory genes. The activity of P-TEFb is tightly regulated within the cells by its association with either HEXIM1 and 7SK snRNA or with Brd4. HEXIM1 and Brd4 are also involved in NF-?B-mediated inflammatory gene expression and cancer formation and are potential targets for drug development. The overall goal of this proposal is to investigate the regulation and functions of these transcription regulators in the H. pylori-mediated inflammatory response and to explore the therapeutic potential for manipulation of these regulators in the prevention and treatment of H. pylori-initiated gastric diseases. In Specific Aim 1, we will investigate the essential role of Brd4 in H. pylori-induced gastric diseases in cultured cells and in animals, which include the Mongolian gerbils and gastric epithelial cell-specific Brd4 conditional knockout mice. We will also explore the therapeutic potential of Brd4 inhibitor JQ1 as a drug for the prevention and treatment of H. pylori-induced inflammatory diseases and gastric cancer. In Specific Aim 2, we will dissect the role of HEXIM1 in the inactivation of NF-?B and in the H. pylori-induced inflammatory response and gastric cancer. We will also examine the possibility of using HMBA to intervene in the H. pylori-induced inflammatory response and initiation of gastric cancer. In Specific Aim 3, we will determine how CDK9 activation is regulated for the efficient transcription of H. pylori-induced inflammatory genes. We will also evaluate the therapeutic potential of CDK9 inhibitor flavopiridol for H. pylori-induced gastric diseases.