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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：
9116935
负责人：
HELEN CHRISTOU
金额：
$ 42.92万
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/9116935
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 Pathogenesis Pathologic Pathway interactions Patient-Focused Outcomes 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 Smooth Muscle 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。肺血管重塑是肺高压发病机制的关键，目前的治疗方法并没有有效地针对肺血管重塑这一疾病的固定成分。肺血管平滑肌细胞(VSMCs)由收缩表型转变为合成/增殖表型和糖酵解表型是PH肺血管重构的重要原因，也可能是其对血管扩张剂反应性差的重要原因。然而，VSMC的表型转换是一个可逆的过程，因此是一个有希望的研究领域，可能导致新的治疗方法，逆转已建立的重塑，并增强对肺血管扩张剂的反应性。因此，了解VSMC分化通路在PH发病机制中的作用及其逆转对于确定此类新的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)转录复合体是VSMC分化的主要调节因子，参与了PH的发病过程，可以作为治疗的靶点。此外，使用两种PH的实验模型，我们发现了一种新的干预方法，即用NH4Cl治疗诱导轻度代谢性酸中毒，导致PH的预防，逆转已建立的重塑，并提高对肺血管扩张剂的反应性。本研究的主要目的是(I)明确Carg-myocardin-血清反应因子(SRF)转录复合体在PH发病机制中的作用及其逆转作用(Ii)研究乙酰唑胺诱导的临床可行酸中毒是否能恢复实验性PH肺VSMC的功能性收缩表型，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转录复合体参与了PH的发病过程，酸中毒通过这一途径恢复了功能性收缩的VSMC表型，从而逆转了病理性肺血管重构。我们的具体目标是：(1)确定Carg-MyoC-SRF转录复合体在实验性PH的发生和逆转中的作用。(2)。验证电针通过Carg-MyoC-SRF转录复合体调控肺VSMC表型转换的假说。(3)。为了验证这样一种假设，即在体内用乙酰唑胺(ACTZ)诱导临床可行的代谢性酸中毒可促进实验性PH患者收缩的肺VSMC表型。我们的研究旨在确定Carg-MyoC-SRF途径中用于治疗PH的新的分子靶点。