MIF-Thyroxine Interactions in the Pathogenesis of Pulmonary Arterial Hypertension

描述(申请人提供)：肺动脉高压(PAH)是一种慢性进行性疾病，导致肺血管重塑、血液中低氧、右侧心力衰竭和死亡。预后不佳和缺乏有效的PAH疾病改良剂，突出表明需要更好地了解疾病的发病机制，以便确定新的治疗方法。这项建议涉及多环芳烃的发展和进展所涉及的分子机制。具体地说，我们将在生理和细胞水平上检查PAH中促炎症细胞因子[巨噬细胞迁移抑制因子(MIF)]和甲状腺激素[甲状腺激素(T4)]之间先前未知的临床相关相互作用的影响。我们已经确认MIF是PAH发生和发展过程中的关键介质，此外，我们还发现T4是MIF炎症活性的天然配体和抑制剂。我们推测，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中无MIF的T4比率，并导致了已报道的在肺动脉高压患者中甲状腺功能减退的高患病率。MIF和T4在血浆中的修饰状态深刻地改变了这些分子与它们各自的细胞受体的相互作用，导致细胞内信号和血管细胞增殖的改变。我们概述了一种涉及临床研究、动物模型和体外评估的多方面方法。我们将研究PAH患者在疾病进展过程中以及在标准化运动挑战前后MIF-T4的关系。我们将在两种肺血管重塑动物模型中进一步研究这些分子之间的相互关系，并在细胞水平上更好地了解相互作用对细胞内信号和细胞复制的影响。该项目的长期目标是利用这些分子之间的关系来开发新的、更有效的治疗方法来治疗这种毁灭性的疾病。虽然这项建议侧重于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直接与MIF增加的其他心肺疾病状态相关，包括中风、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.