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

幽门螺杆菌介导的胃炎症和癌症的转录调控

• 批准号: 8726354
• 负责人: Lin-Feng Chen
• 金额: $ 14.55万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726354
• 关键词: Animal Model; Animals; Binding Proteins; Biological Models; Bromodomain; C-terminal; Cell Culture Techniques; Cells; Chronic; Chronic Gastritis; Complex; Cultured Cells; Development; Disease; Elongation Factor; Epithelial Cells; Gastric mucosa; Gastritis; Gene Expression; Genes; Genetic Transcription; Gerbils; Goals; Helicobacter Infections; Helicobacter pylori; Hexamethylene Bisacetamide; Infection; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Lead; Link; Malignant Neoplasms; Mediating; Molecular; Pathogenesis; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Prevention; Proteins; RNA Polymerase II; Regulation; Risk Factors; Role; Small Nuclear RNA; Stomach; Stomach Diseases; Testing; Therapeutic; Transcription Elongation; Transcriptional Elongation Factors; Transcriptional Regulation; Ubiquitination; Ulcer; activating transcription factor; cancer cell; cancer gene expression; cancer initiation; cyclin T1; drug development; flavopiridol; human disease; in vivo; inhibitor/antagonist; malignant stomach neoplasm; pathogen; public health relevance; response; transcription factor; tumorigenesis

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.

描述（由申请人提供）：幽门螺杆菌感染会导致慢性胃炎和消化性溃疡，并且是发展成胃癌的最强危险因素。 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，其特征是许多炎症基因表达增强。 转录因子 NF-κB 通过调节这些炎症基因的表达，在幽门螺杆菌引发的炎症反应和胃炎中发挥关键作用。 包括我们在内的最近研究表明，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 NF-κB 依赖性炎症基因的表达至关重要。 P-TEFb 的活性在细胞内通过与 HEXIM1 和 7SK snRNA 或与 Brd4 的关联而受到严格调节。 HEXIM1 和 Brd4 还参与 NF-κB 介导的炎症基因表达和癌症形成，是药物开发的潜在靶标。 该提案的总体目标是研究这些转录调节因子在幽门螺杆菌介导的炎症反应中的调节和功能，并探索操纵这些调节因子在预防和治疗幽门螺杆菌引发的胃疾病中的治疗潜力。 在具体目标 1 中，我们将在培养细胞和动物（包括蒙古沙鼠和胃上皮细胞特异性 Brd4 条件敲除小鼠）中研究 Brd4 在幽门螺杆菌诱导的胃疾病中的重要作用。 我们还将探索 Brd4 抑制剂 JQ1 作为预防和治疗幽门螺杆菌引起的炎症性疾病和胃癌的药物的治疗潜力。 在具体目标 2 中，我们将剖析 HEXIM1 在 NF-κB 失活中的作用 以及幽门螺杆菌诱导的炎症反应和胃癌。 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。 在具体目标 3 中，我们将确定如何调节 CDK9 激活以实现幽门螺杆菌诱导的炎症基因的有效转录。 我们还将评估 CDK9 抑制剂 flavopiridol 对幽门螺杆菌引起的胃部疾病的治疗潜力。