MIF-Thyroxine Interactions in the Pathogenesis of Pulmonary Arterial Hypertension

描述（由申请人提供）：肺动脉高压（PAH）是一种慢性进行性疾病，可导致肺血管重塑、血液低氧、右侧心力衰竭和死亡。预后不良和缺乏有效的PAH疾病修饰剂强调需要更好地了解疾病的发病机制，以确定新的治疗方法。该提案涉及PAH发生和进展的分子机制。具体而言，我们将在生理和细胞水平上研究PAH中促炎细胞因子[巨噬细胞迁移抑制因子（MIF）]和甲状腺激素[甲状腺素（T4）]之间先前未识别的临床相关相互作用的影响。我们已经确定了MIF作为PAH发展和进展的关键介质，并且进一步，我们已经令人惊讶地发现T4是MIF炎症活性的天然配体和抑制剂。我们假设在PAH发展过程中观察到的循环MIF的急剧增加改变了正常的血浆无MIF T4比率，并成为肺动脉高压患者中报告的甲状腺功能减退症高患病率的基础。MIF和T4在血浆中的改变状态深刻地改变了这些分子与其各自的细胞受体的相互作用，导致改变的细胞内信号传导和血管细胞增殖。我们概述了一个多方面的方法，涉及临床研究，动物模型和体外评估。我们将研究PAH患者在疾病进展期间和标准化运动挑战前后的MIF-T4关系。我们将进一步研究这些分子之间的相互关系，在两个动物模型的肺血管重塑和在细胞水平上更好地了解细胞内信号和细胞复制的相互作用的后果。该项目的长期目标是利用这些分子之间的关系，开发新的和更有效的治疗方法来治疗这种毁灭性的疾病。虽然该提案侧重于MIF和T4在PAH发病机制中的相互作用，但研究中获得的数据将与MIF增加的其他心肺疾病状态直接相关，包括卒中、心血管疾病、心肌梗死、肺纤维化和阻塞性睡眠呼吸暂停。

DESCRIPTION (provided by applicant): Pulmonary Arterial Hypertension (PAH) is a chronic progressive disorder that leads to remodeling of blood vessels in the lung, low oxygen in the blood, right-sided heart failure and death. The poor prognosis and lack of effective PAH disease-modifying agents underscore the need for a better understanding of disease pathogenesis in order to identify new therapeutic approaches. This proposal addresses the molecular mechanisms involved in the development and progression of PAH. Specifically, we will examine - at both the physiological and the cellular level - the effects of a previously unrecognized, clinically relevant interaction between a proinflammatory cytokine [Macrophage Migration Inhibitory Factor (MIF)] and a thyroid hormone [Thyroxine (T4)] in PAH. We have identified MIF as a critical mediator in the development and progression of PAH and further, we have made the surprising discovery that T4 is a natural ligand for and inhibitor of MIF's inflammatory activity. We hypothesize that the dramatic increase in circulating MIF observed during the development of PAH alters the normal plasma MIF-free T4 ratio and underlies the high prevalence of hypothyroidism that has been reported in patients with pulmonary hypertension. The modified status of MIF and T4 in the plasma profoundly changes the interactions of these molecules with their respective cellular receptors leading to altered intracellular signaling and vascular cell proliferation. We outline a multi-faceted approach involving clinical studies, animal models and in vitro assessments. We will examine the MIF-T4 relationship in patients with PAH, both during disease progression and before/after a standardized exercise challenge. We will further examine the interrelationship between these molecules in both animal models of pulmonary vascular remodeling and at a cellular level to understand better the consequence of the interaction on intracellular signaling and cell replication. The long term goal of the project is to exploit the relationship between these molecules to develop new and more effective therapeutic approaches for the treatment this devastating disease. While this proposal focuses on the interactions of MIF and T4 in the pathogenesis of PAH, data achieved in the study will be directly relevant to other cardiopulmonary disease states in which MIF is increased including stroke, cardiovascular disease, myocardial infarction, pulmonary fibrosis and obstructive sleep apnea.