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Vascular smooth muscle cell phenotypic switching in Pulmonary Hypertension

肺动脉高压中血管平滑肌细胞表型转换

基本信息

批准号：
8918724
负责人：
HELEN CHRISTOU
金额：
$ 42.35万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8918724
关键词：
Acetazolamide Acidosis Ammonium Chloride Animals Apoptosis Area Binding Blood Vessels Cell Differentiation process Complex Cyclic GMP-Dependent Protein Kinases Data Development Differentiation Antigens Disease Effectiveness Electrophoretic Mobility Shift Assay Endothelium Event Experimental Models Goals Health Homeostasis Human Hypoxia In Vitro Intervention Investigation Lead Lung Medial Mediating Mediator of activation protein Messenger RNA Metabolic Metabolic acidosis Modeling Molecular Molecular Target Monocrotaline Nuclear Extract Outcome Pathogenesis Pathologic Pathway interactions Patients Phenotype Pre-Clinical Model Predisposition Prevention Process Proteins Pulmonary Circulation Pulmonary Hypertension Pulmonary artery structure Pulmonary vessels Rattus Reporting Research Design Resistance Rodent Role Serum Response Factor Small Interfering RNA Smooth Muscle Myocytes Testing Therapeutic Intervention Thick Vascular remodeling Vasodilator Agents chromatin immunoprecipitation extracellular gain of function gene delivery system histone modification improved in vivo loss of function migration mortality myocardin new therapeutic target non-viral gene delivery novel novel therapeutics overexpression prevent protective effect research study response restoration therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Pulmonary Hypertension (PH) is a serious disease associated with high mortality. Pulmonary vascular remodeling is key to PH pathogenesis and this fixed component of the disease is not effectively targeted by current therapies. Phenotypic switching of resident pulmonary vascular smooth muscle cells (VSMCs) from a contractile to a synthetic/proliferative and predominantly glycolytic phenotype contributes to pulmonary vascular remodeling in PH and likely underlies poor responsiveness to vasodilators. However, VSMC phenotypic switching is a reversible process and therefore a promising area of investigation that may lead to novel therapies that will reverse established remodeling and enhance responsiveness to pulmonary vasodilators. Understanding the role of VSMC differentiation pathways in PH pathogenesis and its reversal is thus of critical importance in identifying such novel therapeutic molecular targets. Our preliminary data support that the CArG-myocardin (MyoC)-Serum Response Factor (SRF) transcriptional complex, a master regulator of VSMC differentiation, is involved in PH pathogenesis and can be therapeutically targeted. In addition, using two experimental models of PH, we discovered that a novel intervention, using induction of mild metabolic acidosis with NH4Cl treatment, leads to prevention of PH, reversal of established remodeling and improved responsiveness to pulmonary vasodilators. The primary objectives of this proposal are (i) to define the role of the CArG-myocardin-Serum Response Factor (SRF) transcriptional complex in PH pathogenesis and its reversal (ii) to examine whether induction of clinically feasible acidosis with the use of Acetazolamide will restore a functionally contractile pulmonary VSMC phenotype in experimental PH and improve pulmonary vascular responsiveness to vasodilators. Our central hypothesis is that the CArG-MyoC-SRF transcriptional complex is involved in PH pathogenesis and that acidosis reverses pathologic pulmonary vascular remodeling by restoring a functionally contractile VSMC phenotype via this pathway. Our specific aims are: (1) To define the role of the CArG-MyoC- SRF transcriptional complex in the development and reversal of experimental PH. (2). To test the hypothesis that EA modulates pulmonary VSMC phenotype switching via the CArG-MyoC-SRF transcriptional complex. (3). To test the hypothesis that in vivo induction of clinically feasible metabolic acidoss with Acetazolamide (ACTZ) promotes a contractile pulmonary VSMC phenotype in experimental PH. Our studies are designed to identify novel molecular targets in the CArG-MyoC-SRF pathway for therapeutic interventions for PH.

描述（申请人提供）：肺动脉高压（PH）是一种与高死亡率相关的严重疾病。肺血管重塑是PH发病机制的关键，并且该疾病的这一固定组分未被当前疗法有效靶向。驻留肺血管平滑肌细胞（VSMC）从收缩性表型转换为合成/增殖和主要糖酵解表型有助于PH中的肺血管重塑，并可能是对血管扩张剂反应性差的基础。然而，VSMC表型转换是一个可逆的过程，因此是一个有前途的研究领域，可能会导致新的治疗，将扭转建立重塑和增强肺血管扩张剂的反应。因此，了解VSMC分化途径在PH发病机制及其逆转中的作用对于确定此类新型治疗分子靶点至关重要。我们的初步数据支持CArG-myocardin（MyoC）-血清反应因子（SRF）转录复合物，VSMC分化的主要调节因子，参与PH发病机制，并可作为治疗靶点。此外，使用两种PH实验模型，我们发现一种新的干预方法，使用NH 4Cl治疗诱导轻度代谢性酸中毒，可预防PH，逆转已建立的重塑并改善对肺血管扩张剂的反应性。本提案的主要目的是（i）确定CArG-心肌蛋白-血清反应因子（SRF）转录复合物在PH发病机制及其逆转中的作用（ii）检查使用乙酰唑胺诱导临床可行的酸中毒是否会恢复实验性PH中功能性收缩的肺VSMC表型，并改善肺血管对血管扩张剂的反应性。我们的中心假设是CArG-MyoC-SRF转录复合物参与PH的发病机制，酸中毒通过恢复VSMC的功能性收缩表型来逆转病理性肺血管重塑。我们的具体目标是：（1）确定CArG-MyoC- SRF转录复合物在实验性PH发生和逆转中的作用。验证EA通过CArG-MyoC-SRF转录复合物调节肺VSMC表型转换的假设。（三）、为了检验用乙酰唑胺（ACTZ）体内诱导临床可行的代谢酸可促进实验性PH中肺VSMC收缩表型的假设。我们的研究旨在确定CArG-MyoC-SRF途径中的新分子靶点，用于PH的治疗干预。