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

• 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
• 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; 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

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，中风和周围血管疾病的主要触发因素，这仍然是工业化世界中死亡的主要原因。对新型抗动脉粥样硬化药物干预的医疗需求未满足。这项工作中的关键障碍是我们目前无法完全理解动脉粥样硬化中的致病性和调节途径。动脉粥样硬化的重要病理特征之一是平滑肌样细胞的异常积累，所谓的合成平滑肌细胞（SMC）。合成的SMC具有增殖，迁移，分泌，炎症和凋亡，因此在开始，进展和破裂中起关键作用 动脉粥样硬化斑块。我们最近发现，循环核苷酸磷酸二酯酶1C（PDE1C）在疾病血管的合成SMC中特别表达，但在正常脉管系统中却没有表达，而促进性血管固醇血管紧张素II（Ang II）（Ang II）和反应性氧化应激（ROS）可以通过核糖组S6 Kinse s6 kinasse（PDE）（ROS）（ROS）（ROS）激活PDE1C。 PDE1C激活对于介导ANG II诱导的溶酶体胆固醇积累和合成SMC中的趋化因子表达至关重要。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的积累，随后诱导ROS产生并因溶酶体功能障碍引起的胁迫诱导的细胞凋亡。因此，我们将探讨以下假设：PDE1C充当动脉粥样硬化过程中合成SMC的各种亲震源特征的新型临界阳性调节剂。通过详细描述PDE1C调节的SMC发病机理的功能关系，我们旨在阐明动脉粥样硬化发展的新分子机制，并开发用于治疗该疾病的新型治疗策略。为了实现我们的目标并解决我们的假设，我们提出了以下特定目标。在AIM 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PDE1C如何调节溶酶体功能和胆固醇的积累以及炎症反应。在AIM 2中，我们将了解PDE1C如何被P90RSK激活，并在合成SMC的发病机理中建立P90RSK介导的PDE1C激活的生物学联系。在AIM 3中，我们将确定使用全球和SMC特异性PDE1C-KNOCKOUT小鼠在建立完善的动脉粥样硬化小鼠模型中，PDE1C缺乏减弱了动脉粥样硬化病变形成和血管病理。我们还将表征破坏P90RSK介导的PDE1C通过结合位点肽对血管动脉粥样硬化重塑的影响。我们在这里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病理学的新型分子调节机制，以鉴定新型的治疗靶点，并设计新的疗法以抑制Synthetic SMC病理学，因为PDE超级疾病代表了具有非常有吸引力的药物的特定疗法的特定型药物，因此可以抑制PDE SEMC的病理学。