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

描述（由申请方提供）：特发性肺动脉高压（IPAH）是一种致死性疾病，其特征为肺血管收缩和重塑，导致右心室肥大进行性恶化，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的2型受体BMPR 2突变所致。BMPR 2可以通过几种不同的途径进行信号传导，包括SMAD 1/5/8以及p38和p42/44 MAPK。人IPAH患者中的BMPR 2突变经常似乎使SMAD信号完整，而导致p38和p42/44 MAPK组成性激活的突变是常见的。这有力地表明，在人类患者体内，是BMPR 2介导的MAPK抑制的丧失，而不是SMAD信号传导的丧失，导致肺动脉高压表型。因此，我们假设，这是通过BMPR 2的p38和p42/44 MAPK信号的失调，导致血管反应性和肺血管结构的缺陷，PAH的中心标志。本提案的目的是在PAH转基因模型中直接检验这一假设。为此，我们开发了PAH的诱导型平滑肌特异性小鼠模型，其主要在血管反应性（BMPR 2-delx 4+）或肺血管结构（BMPR 2-R899 X）方面存在缺陷。我们打算（目的1）确定是否一个或两个表型可以预防或治疗药理学p38或p42/44 MAPK抑制剂，（目的2）确定的分子通路，BMPR 2连接到升高的p38和p42/44 MAPK，和（目的3）确定通过BMPR 2异常MAPK信号传导的分子后果，使用平滑肌细胞培养这些动物。相关性：来自人类肺动脉高压患者的证据表明，通过BMPR 2的MAPK信号传导缺陷导致疾病。本研究将确定MAPK信号传导缺陷如何以及是否导致这些问题，并将尝试干预措施来预防或治疗。我们将使用新的小鼠模型来做到这一点，这些模型复制了人类疾病的突变和中心特征，以及从这些动物中培养的细胞，目的是开发更有效的疗法。

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.