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

描述(申请人提供)：特发性肺动脉高压是一种以肺血管收缩和重塑为特征的致命性疾病，导致右室肥厚逐渐恶化，最终导致右心衰竭。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突变所致。BMPR2可以通过几种不同的途径发出信号，包括SMAD 1/5/8以及p38和p42/44 MAPK。在人类IPAH患者中，BMPR2突变似乎经常使SMAD信号保持完整，而导致p38和p42/44 MAPK结构性激活的突变是常见的。这有力地表明，在人体内，是BMPR2介导的MAPK抑制的丢失而不是SMAD信号的丢失导致了肺动脉高压的表型。因此，我们推测这是通过BMPR2调节p38和p42/44 MAPK信号的失调，导致了血管反应性和肺血管结构的缺陷，这是PAH的中心特征。这项建议的目的是在PAH的转基因模型中直接检验这一假说。为此，我们建立了可诱导的血管反应性(BMPR2-delx4+)或肺血管结构缺陷(BMPR2-R899X)的PAH小鼠模型。我们打算(目标1)确定药理上的p38或p42/44 MAPK抑制剂是否可以预防或治疗这两种表型中的一种或两种，(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，以及(目标3)利用从这些动物培养的平滑肌细胞确定通过BMPR2异常的MAPK信号的分子后果。相关性：来自人类肺动脉高压患者的证据表明，通过BMPR2的MAPK信号缺陷导致疾病。这项研究将确定MAPK信号缺陷如何以及是否会导致这些问题，并将尝试干预措施以实现预防或治疗。我们将使用复制人类疾病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做到这一点，目标是开发更有效的治疗方法。

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.