PDE10A Regulation and Function in Cardiovascular Disease

PDE10A 在心血管疾病中的调节和功能

• 批准号: 9888405
• 负责人: Bradford C Berk
• 金额: $ 52.32万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-10 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888405
• 关键词: Abnormal Cell; Allografting; Angioplasty; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Bioinformatics; Blood Vessels; Bone Marrow; Bypass; Candidate Disease Gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Carotid Atherosclerotic Disease; Cell Death; Cell Proliferation; Cells; Clinical; Clinical Trials; Coronary Arteriosclerosis; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotides; Data; Deposition; Diffuse; Disease; Disease model; Endothelial Cells; Extracellular Matrix; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Goals; Growth Factor; Human; Hydrolysis; Hyperplasia; Inbred Strains Mice; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Lesion; Ligation; Link; Mediating; Modeling; Mus; Operative Surgical Procedures; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Process; Protein Isoforms; Proteins; Psychomotor Performance; Psychotic Disorders; Public Health; Regulation; Regulatory Element; Risk; Role; Saphenous Vein; Schizophrenia; Signal Transduction; Single Nucleotide Polymorphism; Site; Smooth Muscle Myocytes; Stenosis; Stents; Stimulus; Therapeutic; Thrombosis; Transcription Coactivator; Ubiquitination; Vascular Diseases; Vascular remodeling; Vein graft; cell growth; cytokine; druggable target; femoral artery; genetic approach; genetic association; genome wide association study; genome-wide; in vivo; inhibitor/antagonist; macrophage; mouse genetics; mouse model; myocardin; new therapeutic target; novel therapeutics; phosphoric diester hydrolase; programs; response; restenosis; vascular inflammation; vascular injury

SUMMARY- Intimal hyperplasia characterized by abnormal accumulation of smooth muscle cell (SMC)-like cells and inflammatory cells is a hallmark of vascular occlusive disorders such as post angioplasty restenosis, vein graft atherosclerosis, and allograft vasculopathy. The current therapies with drug-eluting stents to inhibit SMC proliferation and induce SMC death still have problems due to limited endothelial cell regrowth and increased risk of thrombosis. Moreover, drug-eluting stents effective for focal lesions are not appropriate for diffuse atherosclerotic disease. Thus, there is high demand to develop novel therapeutic strategies. Our unbiased genome-wide genetic polymorphism association study in mice has identified cyclic nucleotide phosphodiesterase 10A (PDE10A, catalyzing cyclic nucleotide hydrolysis) as a potential candidate gene contributing to injury-induced intimal hyperplasia. Indeed, PDE10A expression is markedly elevated in the intimal SMC-like cells and macrophages in mouse models of vascular injury and in human atherosclerotic lesions. Our preliminary data with PDE10A knockout mice and PDE10 inhibitor suggest that PDE10A is important in pathological vascular remodeling in vivo. In cultured SMCs, PDE10A depletion or inhibition increases myocardin protein (a master driver of SMC contractile phenotype) and expression of several SMC contractile marker genes. In macrophages, we found that PDE10A is important for NLRP3 inflammasome expression and activation. PDE10A expression is up-regulated by growth factors and inflammatory cytokines. Bioinformatic analysis identified a highly conserved intronic putative transcriptional regulatory sequence at the single-nucleotide polymorphism (SNP) site identified by our mouse genetic association study, and it may be responsible for regulating PDE10A gene expression during phenotype switching and stimulation of inflammation. Thus, we hypothesize that increased PDE10A expression, by inhibiting cAMP signaling, promotes synthetic SMC phenotype transition and macrophage inflammasome expression/activation; and thus stimulates intimal hyperplasia. The overall objective of this proposal is to investigate the mechanisms that regulate expression of PDE10A, and PDE10A's specific role in the processes responsible for intimal hyperplasia. To achieve our goals, two Specific Aims are proposed: (1) Determine the role of PDE10A in intimal formation and vascular remodeling after injury using both genetic and pharmacological approaches. (2) Define the mechanisms for PDE10A regulation of vascular pathology: regulation of PDE10A expression, transition of SMC phenotype, and stimulation of vascular inflammation. PDE10A is well known in psychosis; and PDE10A inhibitor has been developed for clinical trials to treat schizophrenia. However, PDE10A regulation and function in cardiovascular system remains largely unknown. Our studies should yield novel therapeutic strategies to limit pathologic intimal hyperplasia given PDE10A has proved to be a druggable target.

总结-以平滑肌细胞（SMC）样异常积聚为特征的内膜增生 细胞和炎性细胞是血管闭塞性疾病如血管成形术后再狭窄的标志， 静脉移植物动脉粥样硬化和同种异体移植物血管病。目前的药物洗脱支架治疗， SMC增殖和诱导SMC死亡仍然存在问题，这是由于有限的内皮细胞再生长， 增加血栓形成的风险。此外，对局灶性病变有效的药物洗脱支架不适用于 弥漫性动脉粥样硬化疾病因此，存在开发新的治疗策略的高需求。我们 一项在小鼠中进行的无偏全基因组遗传多态性关联研究发现， 磷酸二酯酶10A（PDE 10A，catalyzing cyclic nucleotide hydrolysis）作为一个潜在的候选基因 导致损伤诱导的内膜增生。事实上，PDE 10A的表达在哺乳动物中显著升高。 小鼠血管损伤模型和人动脉粥样硬化中内膜SMC样细胞和巨噬细胞 病变我们对PDE 10A敲除小鼠和PDE 10抑制剂的初步数据表明，PDE 10A是 在体内病理性血管重塑中重要。在培养的SMC中，PDE 10A消耗或抑制 增加心肌蛋白（SMC收缩表型的主要驱动因素）和几种SMC的表达 收缩标记基因在巨噬细胞中，我们发现PDE 10A对NLRP 3炎性小体是重要的， 表达和激活。PDE 10A表达受生长因子和炎性细胞因子上调。 生物信息学分析确定了一个高度保守的内含子假定的转录调控序列， 单核苷酸多态性（SNP）位点通过我们的小鼠遗传关联研究确定，它可能是 负责调节PDE 10A基因表达的表型转换和刺激 炎症因此，我们假设通过抑制cAMP信号传导， 促进合成SMC表型转变和巨噬细胞炎性体表达/激活;因此 刺激内膜增生。本提案的总体目标是调查 调节PDE 10A的表达，以及PDE 10A在负责内膜增生的过程中的特定作用。 增生为了实现我们的目标，提出了两个具体目标：（1）确定PDE 10A在 使用遗传学和药理学方法研究损伤后内膜形成和血管重塑。（二） 定义PDE 10A调节血管病理的机制：PDE 10A表达的调节， SMC表型转变和刺激血管炎症。PDE 10A在精神病中是众所周知的; PDE 10A抑制剂已被开发用于治疗精神分裂症的临床试验。然而，PDE 10A 心血管系统的调节和功能在很大程度上仍是未知的。我们的研究应该产生新的 限制给予PDE 10A的病理性内膜增生的治疗策略已被证明是一种药物治疗策略， 目标