Function and Regulation of Phosphodiesterase in Atherogenesis

磷酸二酯酶在动脉粥样硬化形成中的功能和调节

基本信息

批准号：
8603863
负责人：
Chen Yan
金额：
$ 37.61万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8603863
关键词：
Address Adenylate Cyclase Angiotensin II Apoptosis Apoptotic Arterial Fatty Streak Atherosclerosis Attenuated Binding Sites Biochemical Biochemistry Bioinformatics Biological Blood Vessels Cause of Death Cells Cellular biology Chemotaxis Cholesterol Cyclic AMP Cyclic Nucleotides Dependovirus Development Disease Drug Targeting Functional disorder Gene Expression Goals Inflammatory Inflammatory Response Intervention Knockout Mice Lesion Link Lipids Lysosomes Mediating Medical Molecular Molecular Biology Myocardial Infarction Oxidative Stress Pathogenesis Pathologic Processes Pathology Peptides Peripheral Vascular Diseases Pharmaceutical Preparations Phosphorylation Play Process Production Protein Isoforms Public Health Regulation Regulatory Pathway Relative (related person)Ribosomal Protein S6 Kinase Ribosomes Role Rupture Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stimulus Stress Stroke Technology Therapeutic Therapeutic Agents Vascular Diseases Viagra atherogenesis base chemokine design in vivo innovation macrophage mouse model new therapeutic target novel novel therapeutics phosphoric diester hydrolase public health relevance screening

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is the main trigger of myocardial infarction, stroke and peripheral vascular disease, which remains the leading cause of death in the industrialized world. There is an unmet medical need for novel anti- atherosclerotic drug interventions. A critical roadblock in this endeavor is our current inability to fully understand pathogenic and regulatory pathways in atherogenesis. One of the important pathological features of atherogenesis is abnormal accumulation of smooth muscle-like cells, so-called synthetic smooth muscle cells (SMCs). Synthetic SMCs are proliferatory, migratory, secretory, inflammatory and apoptotic, and thus play critical roles in the initiation, progression and rupture of atherosclerotic plaques. We recently discovered that cyclic nucleotide phosphodiesterase 1C (PDE1C) is specifically expressed in synthetic SMCs of diseased vessels but not in normal vasculature and that proatherogenic stimuli angiotensin II (Ang II) and reactive oxidative stress (ROS) can activate PDE1C through ribosome S6 kinase (p90RSK). PDE1C activation is essential for mediating Ang II-induced lysosomal cholesterol accumulation and chemokine expression in synthetic SMCs. We also found that PDE1C is present in lysosomes and is likely involved in lysosomal destabilization and cholesterol accumulation, which subsequently induce ROS production and stress-induced cell apoptosis due to lysosome dysfunction. We will therefore explore the hypothesis that PDE1C acts as a novel critical positive regulator of various pro-atherogenic features of synthetic SMCs in the atherosclerotic process. By characterizing the functional relationship of PDE1C-regulated SMC pathogenesis in atherosclerosis in detail, we aim to elucidate the novel molecular mechanism of atherosclerosis development, and to develop novel therapeutic strategies for treating this disease. To achieve our goals and address our hypotheses we propose the following Specific Aims. In Aim 1 we will employ an array of biochemistry and cell biology approaches to determine how PDE1C regulates lysosomal function and cholesterol accumulation as well as inflammatory response in synthetic SMCs. In Aim 2 we will understand how PDE1C is activated by p90RSK and establish the biological link of p90RSK-mediated PDE1C activation in pathogenesis of synthetic SMCs. In Aim 3 we will determine the extent to which PDE1C deficiency attenuates atherosclerosis lesion formation and vascular pathologies in a well-established mouse model of atherosclerosis using global and SMC-specific PDE1C-knockout mice. We will also characterize the effects of disrupting p90RSK-mediated PDE1C activation by their binding-site peptide on vascular atherogenic remodeling. The innovative approaches and technologies we propose here will enable us to unveil the novel molecular regulatory mechanisms underlying synthetic SMC pathology in atherogenesis, to identify novel therapeutic targets, and to design new therapies to inhibit synthetic SMC pathologies given that PDE superfamily represents a highly attractive class of drug targets for the development of specific therapeutic agents.

描述（由申请人提供）：动脉粥样硬化是心肌梗塞、中风和外周血管疾病的主要诱因，而这些疾病仍然是工业化国家死亡的主要原因。对于新型抗动脉粥样硬化药物干预的医疗需求尚未得到满足。这项努力的一个关键障碍是我们目前无法完全了解动脉粥样硬化形成的致病和调控途径。动脉粥样硬化形成的重要病理特征之一是平滑肌样细胞，即所谓的合成平滑肌细胞（SMC）的异常积累。合成 SMC 具有增殖性、迁移性、分泌性、炎症性和凋亡性，因此在起始、进展和破裂中发挥着关键作用动脉粥样硬化斑块。我们最近发现环核苷酸磷酸二酯酶 1C (PDE1C) 在病变血管的合成 SMC 中特异性表达，但在正常脉管系统中不表达，并且促动脉粥样硬化刺激血管紧张素 II (Ang II) 和反应性氧化应激 (ROS) 可以通过核糖体 S6 激酶激活 PDE1C。 p90RSK）。 PDE1C 激活对于介导 Ang II 诱导的溶酶体胆固醇积累和合成 SMC 中趋化因子的表达至关重要。我们还发现，PDE1C 存在于溶酶体中，可能参与溶酶体不稳定和胆固醇积累，随后由于溶酶体功能障碍而诱导 ROS 产生和应激诱导的细胞凋亡。因此，我们将探讨以下假设：PDE1C 在动脉粥样硬化过程中充当合成 SMC 各种促动脉粥样硬化特征的新型关键正调节因子。通过详细描述PDE1C调节的SMC发病机制在动脉粥样硬化中的功能关系，我们的目的是阐明动脉粥样硬化发展的新分子机制，并开发治疗该疾病的新治疗策略。为了实现我们的目标并解决我们的假设，我们提出以下具体目标。在目标 1 中，我们将采用一系列生物化学和细胞生物学方法来确定 PDE1C 如何调节合成 SMC 中的溶酶体功能和胆固醇积累以及炎症反应。在目标 2 中，我们将了解 PDE1C 如何被 p90RSK 激活，并建立 p90RSK 介导的 PDE1C 激活在合成 SMC 发病机制中的生物学联系。在目标 3 中，我们将使用整体和 SMC 特异性 PDE1C 敲除小鼠，确定 PDE1C 缺陷在完善的动脉粥样硬化小鼠模型中减弱动脉粥样硬化病变形成和血管病理的程度。我们还将表征通过其结合位点肽破坏 p90RSK 介导的 PDE1C 激活对血管动脉粥样硬化重塑的影响。鉴于 PDE 超家族是一个极具吸引力的类别，我们在此提出的创新方法和技术将使我们能够揭示动脉粥样硬化中合成 SMC 病理学背后的新分子调节机制，识别新的治疗靶点，并设计新的疗法来抑制合成 SMC 病理学用于开发特定治疗药物的药物靶标。