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.

内容提要--以血管内皮细胞(SMC)样异常积聚为特征的内膜增生 细胞和炎症细胞是血管闭塞性疾病的标志，如血管成形术后再狭窄， 移植静脉动脉粥样硬化和同种异体移植血管病变。药物洗脱支架抑制作用的治疗现状 SMC增殖和诱导SMC死亡仍存在问题，原因是内皮细胞再生有限和 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症。因此，开发新的治疗策略的需求很高。我们的 小鼠全基因组遗传多态关联无偏研究已确定环核苷酸 磷酸二酯酶10A(PDE10A，催化环核苷酸水解)是一个潜在的候选基因 导致损伤所致的内膜增生。事实上，PDE10A在卵巢癌中的表达显著升高。 小鼠血管损伤模型和人动脉粥样硬化模型中内膜SMC样细胞和巨噬细胞的研究 损伤。我们对PDE10A基因敲除小鼠和PDE10抑制剂的初步数据表明，PDE10A是 在体内病理性血管重塑中起重要作用。在培养的SMC中，PDE10A耗尽或抑制 增加肌钙蛋白(SMC收缩表型的主要驱动力)和几种SMC的表达 收缩标记基因。在巨噬细胞中，我们发现PDE10A对于NLRP3炎症体是重要的 表达和激活。PDE10A的表达受生长因子和炎性细胞因子的上调。 生物信息学分析确定了一个高度保守的内含子假定转录调控序列 我们的小鼠遗传关联研究发现了单核苷酸多态(SNP)位点，它可能是 负责调节PDE10A基因在表型转换和刺激过程中的表达 发炎。因此，我们假设，通过抑制cAMP信号，增加PDE10A的表达， 促进合成的SMC表型转变和巨噬细胞炎症体的表达/激活，从而 刺激血管内膜增生。这项提案的总体目标是调查 PDE10A的表达调控及其在血管内膜调控中的作用 增生症。为了实现我们的目标，提出了两个具体的目标：(1)确定PDE10A在 用遗传学和药理学方法研究损伤后内膜形成和血管重塑。(2) 明确PDE10A调节血管病理的机制：调节PDE10A的表达， SMC表型转化，刺激血管炎症。PDE10A在精神病中广为人知； PDE10A抑制剂已被开发用于治疗精神分裂症的临床试验。然而，PDE10A 心血管系统的调节和功能在很大程度上仍不清楚。我们的研究应该产生新奇的东西 PDE10A用于限制病理性内膜增生的治疗策略已被证明是一种可用药 目标。