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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