PDE10A Regulation and Function in Cardiovascular Disease

PDE10A 在心血管疾病中的调节和功能

基本信息

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
项目类别：
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

项目摘要

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.

摘要-以平滑肌细胞 (SMC) 样异常积累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，例如血管成形术后再狭窄，静脉移植动脉粥样硬化和同种异体移植血管病变。目前的治疗方法是使用药物洗脱支架来抑制由于内皮细胞再生有限，SMC 增殖和诱导 SMC 死亡仍然存在问题血栓形成的风险增加。此外，对局灶性病变有效的药物洗脱支架并不适合弥漫性动脉粥样硬化性疾病。因此，迫切需要开发新的治疗策略。我们的小鼠中无偏倚的全基因组遗传多态性关联研究确定了环核苷酸磷酸二酯酶10A（PDE10A，催化环核苷酸水解）作为潜在的候选基因导致损伤引起的内膜增生。事实上，PDE10A 表达在小鼠血管损伤模型和人类动脉粥样硬化模型中的内膜 SMC 样细胞和巨噬细胞病变。我们对 PDE10A 敲除小鼠和 PDE10 抑制剂的初步数据表明，PDE10A 在体内病理性血管重塑中发挥重要作用。在培养的 SMC 中，PDE10A 耗尽或抑制增加心肌蛋白（SMC 收缩表型的主要驱动因素）和多种 SMC 的表达收缩标记基因。在巨噬细胞中，我们发现 PDE10A 对于 NLRP3 炎症小体很重要表达和激活。 PDE10A 表达受到生长因子和炎症细胞因子的上调。生物信息分析鉴定了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性（SNP）位点，它可能是负责在表型转换和刺激过程中调节 PDE10A 基因表达炎。因此，我们假设通过抑制 cAMP 信号传导增加 PDE10A 表达，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。该提案的总体目标是研究以下机制：调节 PDE10A 的表达，以及 PDE10A 在负责内膜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 PDE10A 在使用遗传和药理学方法进行损伤后的内膜形成和血管重塑。 (2) 定义 PDE10A 调节血管病理学的机制：PDE10A 表达的调节， SMC 表型的转变和血管炎症的刺激。 PDE10A 在精神病领域广为人知； 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仍然很大程度上未知。我们的研究应该产生新颖的成果限制 PDE10A 病理性内膜增生的治疗策略已被证明是一种可药物治疗目标。