Inflammatory Gene Regulation in Diabetic Conditions

糖尿病中的炎症基因调控

• 批准号: 8034544
• 负责人: RAMA NATARAJAN
• 金额: $ 10万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-23 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034544
• 关键词: Advanced Glycosylation End Products; Arts; Blood Vessels; Cardiovascular Diseases; Chromatin; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Diabetic Angiopathies; Epigenetic Process; Event; Functional disorder; Funding; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Glucose; Histone Acetylation; In Vitro; Inflammatory; Insulin Resistance; Knowledge; Lead; Letters; Ligands; Mediating; Messenger RNA; Metabolic syndrome; MicroRNAs; Molecular; Names; Nuclear; Pathology; Principal Investigator; Publishing; RNA-Binding Proteins; Research; Role; Stimulus; Testing; Transcription Coactivator; base; chemokine; chromatin remodeling; cytokine; diabetic; diabetic patient; histone modification; in vivo; innovation; insight; mRNA Stability; macrophage; monocyte; new therapeutic target; novel; programs; promoter

DESCRIPTION (provided by applicant): Diabetes, insulin resistance and the metabolic syndrome are associated with significantly accelerated rates of cardiovascular disease. Abnormal activation of circulating monocytes triggered by inflammatory cytokines and chemokines has been implicated in this pathology but the underlying molecular mechanisms are not fully understood. In the previous funding period, we provided the first evidence that diabetic conditions in vitro and in vivo lead to inflammatory gene transcription in monocytes via novel nuclear chromatin remodeling and potential epigenetic mechanisms involving co-operative effects between transcription factors, coactivators and chromatin histone acetylation. We evaluated monocytes cultured in vitro with diabetic stimuli such as high glucose (HG) and ligands of advanced glycation end products (AGEs), as well as monocytes from diabetic patients. We have made excellent progress and completed most of our original Specific Aims and also initiated several new studies. This rapidly moving and dynamic field has opened several new avenues that will be investigated in this renewal. We have uncovered exciting new mechanisms of inflammatory gene expression in monocytes under diabetic conditions including the involvement of novel chromatin factors, and key microRNAs (mIRs) whose targets modulate chromatin remodeling as well as mRNA stability. The current renewal will thus take our studies to a new pioneering level and advance the field by unraveling hitherto unexplored mechanisms of regulation of genes associated with monocyte dysfunction in vitro and in vivo in diabetes. The hypothesis is that diabetic conditions lead to increased expression of inflammatory genes in monocyte /macrophages via transcriptional mechanisms involving chromatin histone modifications and miRs, as well as post-transcriptional mechanisms involving mRNA stabilization. This will be evaluated by 4 Specific Aims based on published and extensive new preliminary data. Aims 1 and 2 will determine how diabetic conditions in vitro in cultured monocytes and in vivo in monocytes from diabetic subjects lead to the transcription of inflammatory genes via novel changes in the chromatin at these gene promoters. Aim 3 will test the functional roles of two key new micro-RNAs (miRs) that are differentially regulated in diabetic monocytes /macrophages. Aim 4 will examine new post-transcriptional mechanisms by which diabetic stimuli increase the stability of key inflammatory gene mRNAs via novel interplay between RNA binding proteins and miRs. Our state-of-the-art and innovative assessments of the cross-talk between the transcriptome, epigenome, ribo-gnome and the inflammasome can provide new insights into cellular events mediating monocyte dysfunction under diabetic and insulin resistant conditions. These completed studies can greatly advance our knowledge of diabetic vascular disease and uncover new therapeutic targets for the debilitating vascular complications of diabetes.

描述（由申请人提供）：糖尿病、胰岛素抵抗和代谢综合征与心血管疾病发病率显着加快有关。由炎性细胞因子和趋化因子引发的循环单核细胞的异常激活与这种病理学有关，但其潜在的分子机制尚不完全清楚。在之前的资助期间，我们提供了第一个证据，表明体外和体内的糖尿病状况通过新型核染色质重塑和涉及转录因子、共激活剂和染色质组蛋白乙酰化之间的协同作用的潜在表观遗传机制导致单核细胞中炎症基因转录。我们评估了在糖尿病刺激下体外培养的单核细胞，例如高葡萄糖（HG）和晚期糖基化终末产物（AGE）的配体，以及来自糖尿病患者的单核细胞。我们取得了巨大的进展，完成了大部分最初的具体目标，并启动了几项新的研究。这个快速发展和充满活力的领域开辟了几个新的途径，将在本次更新中进行研究。我们发现了糖尿病条件下单核细胞炎症基因表达的令人兴奋的新机制，包括新型染色质因子和关键 microRNA (mIR) 的参与，其目标是调节染色质重塑以及 mRNA 稳定性。因此，当前的更新将把我们的研究带到一个新的开创性水平，并通过阐明迄今为止尚未探索的与糖尿病体外和体内单核细胞功能障碍相关的基因调节机制来推进该领域的发展。假设糖尿病通过涉及染色质组蛋白修饰和 miR 的转录机制以及涉及 mRNA 稳定的转录后机制导致单核细胞/巨噬细胞中炎症基因的表达增加。这将根据已发布的广泛新初步数据通过 4 个具体目标进行评估。目标 1 和 2 将确定体外培养的单核细胞和体内糖尿病受试者的单核细胞中的糖尿病状况如何通过这些基因启动子处染色质的新变化导致炎症基因的转录。目标 3 将测试在糖尿病单核细胞/巨噬细胞中受到差异调节的两种关键新 micro-RNA (miR) 的功能作用。目标 4 将研究新的转录后机制，糖尿病刺激通过 RNA 结合蛋白和 miR 之间的新相互作用来增加关键炎症基因 mRNA 的稳定性。我们对转录组、表观基因组、核糖基因组和炎症小体之间的串扰进行最先进和创新的评估，可以为糖尿病和胰岛素抵抗条件下介导单核细胞功能障碍的细胞事件提供新的见解。这些已完成的研究可以极大地增进我们对糖尿病血管疾病的认识，并发现糖尿病血管并发症的新治疗靶点。