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

• 批准号: 7492231
• 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
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7492231
• 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

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）是一种以肺血管收缩和重塑为特征的致命性疾病，可导致逐渐加重的右心室肥厚，最终导致右心衰。IPAH的家族性形式通常是由于骨形态发生蛋白途径的2型受体BMPR2的突变。BMPR2可以通过几种不同的途径发出信号，包括SMAD 1/5/8和p38和p42/44 MAPK。人类IPAH患者的BMPR2突变通常会使SMAD信号保持完整，而导致p38和p42/44 MAPK组成性激活的突变则很常见。这有力地表明，在人类患者体内，是bmpr2介导的MAPK抑制的丧失，而不是SMAD信号的丧失，导致了肺动脉高压表型。因此，我们假设p38和p42/44 MAPK信号通过BMPR2的失调导致血管反应性和肺血管结构的缺陷，这是PAH的中心标志。本提案的目的是在多环芳烃转基因模型中直接验证这一假设。为此，我们开发了可诱导的平滑肌特异性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）确定药理学p38或p42/44 MAPK抑制剂是否可以预防或治疗这两种表型，（目标2）确定将BMPR2与p38和p42/44 MAPK升高联系起来的分子途径，（目标3）确定通过BMPR2通过这些动物培养的平滑肌细胞异常的MAPK信号的分子后果。相关性：来自人肺动脉高压患者的证据表明，通过BMPR2的MAPK信号缺陷导致疾病。本研究将确定MAPK信号缺陷如何以及是否会导致这些问题，并将尝试干预措施来预防或治疗这些问题。我们将使用复制突变和人类疾病中心特征的新小鼠模型，以及从这些动物身上培养的细胞来实现这一目标，以开发更有效的治疗方法。