Interactions of SERCA2a and BMPRII in Vascular Disease

SERCA2a 和 BMPRII 在血管疾病中的相互作用

基本信息

批准号：
9160201
负责人：
Lahouaria HADRI
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9160201
关键词：
ATP2A2 Ablation Adenoviruses Affect Animal Model Apoptosis Arteries Attenuated Binding Biopsy Blood Vessels Ca(2+)-Transporting ATPase Calcium Cell Proliferation Cells Cessation of life Chronic Clinical Complex Dependovirus Development Disease Endoplasmic Reticulum Endothelial Cells Endothelium Evaluation Failure Family Fibrosis Functional disorder Gene Expression Regulation Gene Transfer Genes Goals Heart Heart failure Homeostasis Human Hypertrophy Hypoxia In Vitro Inflammation Investigation KDR gene Kinetics Knock-in Mouse Knockout Mice Knowledge Lead Light Link LoxP-flanked allele Lung Messenger RNA Modality Modeling Monocrotaline Mus Muscle Mutation Myosin Heavy Chains NOS3 gene Pathogenesis Pathologic Pathway interactions Patients Phenotype Physiologic intraventricular pressure Play Proteins Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Pump Rattus Reticulum Role STAT3 gene SU 5416 Sampling Serotyping Signal Pathway Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Spatial Distribution Syndrome Testing Tetanus Helper Peptide Therapeutic Therapeutic Effect Therapeutic Intervention Transforming Growth Factor beta Transgenic Animals Transgenic Organisms Vascular Diseases Vascular Proliferation Vascular remodeling Ventricular aerosolized arteriole base bone morphogenetic protein receptors cell growth design disease phenotype gene therapy intimal medial thickening knock-down loss of function loss of function mutation member migration mouse model mutant novel therapeutics overexpression premature primary pulmonary hypertension pulmonary arterial hypertension research study restoration targeted treatment trafficking treatment effect vasoconstriction

项目摘要

Pulmonary arterial hypertension (PAH) is characterized by an increase of pulmonary vascular resistance leading to right ventricular overload and eventually to right ventricular failure and premature death. The pathological mechanisms underlying this condition remains incompletely understood. While the exact causes of PAH remain under investigation, it is widely recognized that the hallmarks of all forms of PH are sustained vasoconstriction, endothelium dysfunction and vascular remodeling. Remodeling of pulmonary arteries is characterized to varying degrees by thickening of the intimal and medial layer of muscular vessels resulting from proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) with alterations in Ca2+ homeostasis. Diverse loss-of-function mutations in the conical BMPR2 gene, a component of the transforming growth factor beta (TGFβ) family that plays a key role in cell growth and fibrosis, have been associated with the majority of familial and sporadic cases of PAH. We have shown that sarco(endo)plasmic reticulum Ca2+- ATPase 2a (SERCA2a) pump expression is decreased in small hypertrophied pulmonary arterioles from patients with PAH and in a rat model of monocrotaline (MCT)-induced PAH. We also found that SERCA2a expression is reduced in hypertrophied pulmonary arterial wall of patients with underlying BMPR2 mutations and in transgenic SM22-tet-BMPR2delx4 mice, with a SMC-specific mutant form of BMPR2, known to develop spontaneous PAH. Gene transfer of SERCA2a by an adenovirus resulted in decreased human PASMC proliferation and migration via a mechanism involving STAT3/NFAT signaling pathways. In addition, SERCA2a overexpression increased BMPR2, eNOS expression and activity and decreased STAT3/NFAT activity in hPAEC. In addition, selective pulmonary SERCA2a gene transfer using aerosolized adeno-associated virus serotype 1 (AAV1.SERCA2a) in MCT-PAH rat model attenuate pulmonary hypertension and RV hypertrophy, and increased eNOS and BMPR2 expression. Based upon the preliminary findings we contend there is cross talk between SERCA2a and BMPR2 with interdependent downstream signaling in pulmonary vascular that affects pulmonary vascular structural remodeling and suggest that SERCA2a gene transfer may modulate BMPR2 expression and/or dependent signaling pathways and therefore PAH phenotype. To test this hypothesis we will: 1) Characterize the link between SERCA2a and BMPR2 in pulmonary vascular cells. 2) Determine the effects of SERCA2-specific ablation in SMCs & ECs on PAH pathogenesis in a mouse model. And 3) Investigate the therapeutic effects of SERCA2a overexpression using chemically modified messenger RNA (modRNA) in transgenic animal models. The knowledge acquired through this proposal is significant because by modulating SERCA2a expression, we will characterize its key role in BMPR2 expression and signaling and therefore in pulmonary vascular remodeling and PAH phenotype, that may lead to the identification of new potential targets for therapeutic intervention to overcome the pathological feature of PAH.

肺动脉高压（PAH）的特征是肺血管抗性的增加导致右心室超负荷，有时会导致右心室衰竭和过早死亡。这这种情况下的病理机制尚未完全理解。而确切原因 PAH仍在调查中，人们广泛认识到所有形式的pH值的标志是维持的血管收缩，内皮功能障碍和血管重塑。肺动脉的重塑是由于肌肉血管的内膜和内侧层增厚，其特征在不同程度上表征从肺动脉平滑肌细胞（PASMC）的增殖和迁移中，CA2+改变稳态。锥形BMPR2基因中的功能丧失突变，转化的一个组成部分生长因子β（TGFβ）家族在细胞生长和纤维化中起关键作用，与 PAH的大多数家庭和零星案件。我们已经表明sarco（endo）等离子网状Ca2+ - 在小的肥大肺动脉菌中，ATPase 2a（SERCA2A）泵表达降低患有PAH的患者和在大鼠单蛋白（MCT）诱导的PAH中。我们还发现SERCA2A 基础BMPR2突变患者的肥大肺动脉壁中的表达降低在具有SMC特异性突变体BMPR2的转基因SM22-TET-BMPR2DELX4小鼠中，已知会发展赞助PAH。腺病毒对SERCA2A的基因转移导致人类PASMC降低通过涉及STAT3/NFAT信号通路的机制增殖和迁移。此外，SERCA2A 过表达增加了BMPR2，ENOS表达和活性，并降低了STAT3/NFAT活性 HPAEC。此外，使用雾化腺相关病毒选择性肺SERCA2A基因转移 MCT-PAH大鼠模型中的血清型1（AAV1.Serca2a）减弱肺动脉高压和RV肥大，并增加了eNOS和BMPR2表达。根据初步发现，我们认为有十字架 SERCA2A和BMPR2之间的对话与肺血管中相互依存的下游信号传导影响肺血管结构重塑，并建议SERCA2A基因转移可能调节 BMPR2表达和/或依赖性信号通路，因此PAH表型。测试这个假设我们将：1）表征肺血管细胞中SERCA2A和BMPR2之间的联系。 2）确定SERCA2特异性消融在SMCS＆EC中对小鼠模型中PAH发病机理的影响。 3）使用化学修饰的使者研究SERCA2A过表达的治疗作用转基因动物模型中的RNA（modRNA）。通过此提案获得的知识很重要因为通过调节SERCA2A的表达，我们将表征其在BMPR2表达和信号传导，因此在肺血管重塑和PAH表型中，可能导致鉴定热干预的新潜在靶标，以克服PAH的病理特征。