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：
9750786
负责人：
Lahouaria HADRI
金额：
$ 47.67万
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/9750786
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 Chemicals 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 Medial 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 Structure 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 cell motility design disease phenotype endothelial dysfunction experimental study gene therapy knock-down loss of function loss of function mutation member migration mouse model mutant novel therapeutics overexpression premature primary pulmonary hypertension pulmonary arterial hypertension 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）的特点是肺血管阻力增加导致右心室负荷过重，最终导致右心室衰竭和过早死亡。这种情况的病理机制仍不完全清楚，而确切原因仍不完全清楚。肺动脉高压的病因仍在调查中，人们普遍认为所有形式的肺动脉高压的特征都持续存在血管收缩、内皮功能障碍和肺动脉重塑。不同程度地表现为肌血管内膜和内侧层增厚，从而导致来自肺动脉平滑肌细胞 (PASMC) 的增殖和迁移以及 Ca2+ 的改变圆锥形 BMPR2 基因（转化的一个组成部分）中存在多种功能丧失突变。生长因子β (TGFβ) 家族在细胞生长和纤维化中起关键作用，与我们已经证明，大多数家族性和散发性 PAH 病例的肌（内）质网 Ca2+-。肥大的小肺动脉中 ATP 酶 2a (SERCA2a) 泵表达减少在 PAH 患者和野百合碱 (MCT) 诱导的 PAH 大鼠模型中，我们还发现了 SERCA2a。具有潜在 BMPR2 突变的肥厚肺动脉壁患者的表达减少在转基因 SM22-tet-BMPR2delx4 小鼠中，具有 BMPR2 的 SMC 特异性突变形式，已知会产生腺病毒 SERCA2a 的基因转移导致人类 PASMC 减少。通过涉及 STAT3/NFAT 信号通路的机制进行增殖和迁移。过表达增加了 BMPR2、eNOS 的表达和活性，并降低了 STAT3/NFAT 活性此外，使用雾化腺相关病毒进行选择性肺部 SERCA2a 基因转移。 MCT-PAH 大鼠模型中的血清型 1 (AAV1.SERCA2a) 可减轻肺动脉高压和右心室肥厚， eNOS 和 BMPR2 表达增加根据初步发现，我们认为存在交叉。 SERCA2a 和 BMPR2 之间的对话与肺血管中相互依赖的下游信号传导影响肺血管结构重塑并表明 SERCA2a 基因转移可能会调节 BMPR2 表达和/或依赖性信号通路以及 PAH 表型来测试这一点。假设我们将：1) 描述肺血管细胞中 SERCA2a 和 BMPR2 之间的联系。确定 SMC 和 EC 中 SERCA2 特异性消融对小鼠模型 PAH 发病机制的影响。 3) 使用化学修饰的信使研究 SERCA2a 过度表达的治疗效果转基因动物模型中的 RNA (modRNA) 通过该提案获得的知识非常重要。因为通过调节 SERCA2a 表达，我们将表征其在 BMPR2 表达中的关键作用，并且信号传导，因此在肺血管重塑和 PAH 表型中，这可能导致确定新的潜在治疗干预目标，以克服 PAH 的病理特征。