Role of p38 and p42/44 MAPK in Pulmonary Arterial Hypertension

p38 和 p42/44 MAPK 在肺动脉高压中的作用

基本信息

批准号：
7317437
负责人：
JAMES D WEST
金额：
$ 38.38万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7317437
关键词：
Animal Model Animals Arteries BMPR2 gene Biological Markers Blood Vessels Characteristics Continuous Infusion Cultured Cells Cytokine Signaling Data Defect Development Disease Dominant-Negative Mutation Doxycycline Endothelin Receptor Antagonist Epoprostenol Etiology Genes Genetic Transcription Goals Growth Heart failure Human Immediate-Early Genes In Vitro Inflammatory Intervention Lead Left Lesion Link Lung MAP Kinase Gene MAPK14 gene Mediating Mitogen-Activated Protein Kinase Inhibitor Molecular Molecular Target Mus Muscle Mutation Oral Organ Pathogenesis Pathway interactions Patients Phenotype Phospho-Specific Antibodies Physiologic intraventricular pressure Physiological Play Prevention Protein Overexpression Pulmonary Hypertension Purpose Regulation Research Personnel Resistance Right Ventricular Hypertrophy Role Signal Transduction Signal Transduction Pathway Smooth Muscle Smooth Muscle Myocytes Structure Tars Testing Tetanus Helper Peptide Transgenic Mice Transgenic Model Transgenic Organisms Work bone morphogenic protein human disease human study improved in vivo inhibitor/antagonist innovation mouse Smc1l1 protein mouse Smc1l2 protein mouse model novel pressure prevent programs pulmonary arterial hypertension receptor response vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Idiopathic pulmonary arterial hypertension (IPAH) is a lethal disorder characterized by pulmonary vasoconstriction and remodeling, leading to progressively worsening right ventricular hypertrophy, and eventually right heart failure. The familial form of IPAH is usually due to mutations in the type 2 receptor for the bone morphogenic protein pathway, BMPR2. BMPR2 can signal through several different pathways, including SMAD 1/5/8 and both p38 and p42/44 MAPK. The BMPR2 mutations in human IPAH patients frequently appear to leave SMAD signaling intact, whereas mutations leading to constitutive activation of both p38 and p42/44 MAPK are common. This strongly suggests that, in vivo in human patients, it is loss of BMPR2-mediated suppression of MAPK, rather than loss of SMAD signaling, that leads to the pulmonary hypertensive phenotype. We therefore hypothesize that it is dysregulation of p38 and p42/44 MAPK signaling through BMPR2 which leads to defects both in vasoreactivity and in pulmonary vascular structure, the central hallmarks of PAH. The purpose of this proposal is to directly test this hypothesis in transgenic models of PAH. To do this, we have developed inducible smooth muscle-specific mouse models of PAH which have defects primarily in vasoreactivity (BMPR2-delx4+) or in pulmonary vascular structure (BMPR2-R899X). We intend to (aim 1) determine whether either or both of the phenotypes can be prevented or treated with pharmacologic p38 or p42/44 MAPK inhibitors, (aim 2) determine the molecular pathways that link BMPR2 to elevated p38 and p42/44 MAPK, and (aim 3) determine the molecular consequences of aberrant MAPK signaling through BMPR2, using smooth muscle cells cultured from these animals. Relevance: Evidence from human pulmonary arterial hypertension patients suggests that defective MAPK signaling through BMPR2 causes disease. This study will determine how and whether defective MAPK signaling results in these problems, and will attempt interventions to effect prevention or treatment. We will do this using new mouse models which replicate both the mutations and the central characteristics of human disease, as well as cells cultured from these animals, with the goal of developing more effective therapies.

描述（由申请人提供）：特发性肺动脉高压（IPAH）是一种致命性疾病，其特征是肺血管收缩和重塑，导致右心室肥大逐渐恶化，并最终导致右心衰竭。家族性 IPAH 通常是由于骨形态发生蛋白途径 BMPR2 的 2 型受体突变所致。 BMPR2 可以通过多种不同的途径发出信号，包括 SMAD 1/5/8 以及 p38 和 p42/44 MAPK。人类 IPAH 患者中的 BMPR2 突变通常会使 SMAD 信号保持完整，而导致 p38 和 p42/44 MAPK 组成型激活的突变很常见。这强烈表明，在人类患者体内，导致肺动脉高压表型的是BMPR2介导的MAPK抑制的丧失，而不是SMAD信号传导的丧失。因此，我们假设 p38 和 p42/44 MAPK 信号通过 BMPR2 的失调导致了血管反应性和肺血管结构的缺陷，这是 PAH 的核心特征。该提案的目的是在 PAH 转基因模型中直接检验这一假设。为此，我们开发了可诱导平滑肌特异性 PAH 小鼠模型，该模型主要在血管反应性 (BMPR2-delx4+) 或肺血管结构 (BMPR2-R899X) 方面存在缺陷。我们打算（目标 1）确定是否可以用药物 p38 或 p42/44 MAPK 抑制剂来预防或治疗其中一种或两种表型，（目标 2）确定将 BMPR2 与升高的 p38 和 p42/44 MAPK 联系起来的分子途径，（目标 3）使用从这些动物中培养的平滑肌细胞确定通过 BMPR2 异常 MAPK 信号传导的分子后果。相关性：来自人类肺动脉高压患者的证据表明，通过 BMPR2 的 MAPK 信号传导缺陷会导致疾病。这项研究将确定 MAPK 信号传导缺陷如何以及是否会导致这些问题，并尝试采取干预措施来实现预防或治疗。我们将使用复制人类疾病的突变和核心特征的新小鼠模型以及从这些动物培养的细胞来实现这一目标，目标是开发更有效的疗法。