Hormonal, Metabolic and Signaling Interactions in PAH

摘要 肺动脉高压是一种致命的疾病，对成千上万的患者和 家人。我们团队对这种悲剧性疾病已经研究了30多年，并取得了进步的知识 从这项工作中衍生出来的现在有望极大地改善结果。 我们的总体主题是开发和应用针对以下机制的治疗方法 肺动脉高压(PAH)。我们的研究表明，雌激素信号的改变，以及 细胞内转运和胰岛素抵抗，独立和协同作用，推动血管 以PAH为特征的功能障碍。我们的假设是集中治疗荷尔蒙和新陈代谢 在PAH基础上的紊乱将改善肺血管功能和患者预后。 我们的更新计划包括3个项目和2个核心。项目1从周期1(性激素在 肺动脉高压)。它探索了从理解直接的 性激素对发病机制和风险的贡献按性别划分。我们希望能证实雌激素抑制 他莫昔芬治疗PAH安全有效。项目2也是从周期1(新陈代谢功能)开始的 肺血管疾病)，并从我们对无序的重要性的新认识中浮现出来 血糖控制、胰岛素抵抗和代谢综合征是导致PAH的因素。我们希望确认 二甲双胍和运动对PAH是安全和有益的，并测量患者个体决定因素 回应。项目3是新的(多环芳烃反应的基因组和循环预测因子--带头人安娜·赫姆尼斯医学博士) 我们开发它的目标是在PAH领域推进精准医学，而我们在这方面有着独特的定位。 有一个巨大的未得到满足的需要，需要一个科学的基础，以量身定做的治疗方法，为PAH。我们的长期计划 未来的目标是通过了解影响反应的个体决定因素来优化PAH治疗， 我们的实验疗法(他莫昔芬、二甲双胍、ACE2)以及批准的药物类别(前列环素、 内皮素阻滞剂和磷酸二酯酶抑制剂)。 现在是转换我们在理解PAH机制方面的连续进展的理想时机，因为 负责任的途径被批准的药物(他莫昔芬、二甲双胍)或锻炼作为靶点，这些药物是安全和 在人类中是可以容忍的，我们的团队经验丰富，充满动力。无论是研究还是干预措施都不能 在不考虑疾病分子基础的所有方面的情况下最有效，这是唯一可能的 在一个高度互动的节目中，就像我们在这里建议的那样。

SUMMARY Pulmonary Arterial Hypertension is a lethal disease with devastating impact on thousands of patients and families. Our team has studied this tragic disease for more than 3 decades and the progressive knowledge derived from that work now promises to greatly improve outcomes. Our overall theme is to develop and apply therapies which are directed against mechanisms central to Pulmonary Arterial Hypertension (PAH). Our studies indicate that altered estrogen signalling, and defects in intracellular trafficking and insulin resistance, work independently and in concert to drive the vascular dysfunction characteristic of PAH. Our hypothesis is that focused treatment of the hormonal and metabolic derangements which underlie PAH will improve pulmonary vascular function and patient outcomes. Our renewal program includes 3 Projects and 2 Cores. Project 1 is continued from cycle 1 (Sex Hormones in Pulmonary Arterial Hypertension). It explores exciting avenues derived from understanding the direct contribution of sex hormones to pathogenesis and risk by gender. We expect to confirm that estrogen inhibition with tamoxifen is safe and beneficial in PAH. Project 2 is also continued from cycle 1 (Metabolic Function in Pulmonary Vascular Disease) and emerges from our new understanding of the importance of disordered glucose control, insulin resistance and the metabolic syndrome as contributors to PAH. We expect to confirm that metformin and exercise are safe and beneficial in PAH, and to measure individual patient determinants of response. Project 3 is new (Genomic and Circulating Predictors of PAH response - Leader Anna Hemnes MD) which we developed with the goal to advance precision medicine in PAH, for which we are uniquely positioned. There exists a great unmet need for a scientific basis to tailor the treatment approach for PAH. Our longterm future goal is to optimize PAH therapy by understanding the individual determinants of response, for each of our experimental therapies (tamoxifen, metformin, ACE2) as well as approved agent classes (prostacyclins, endothelin blockers, and phosphodiesterase inhibitors). This is an ideal time to translate our successive progress in understanding PAH mechanisms, because the responsible pathways are targeted by approved drugs (tamoxifen, metformin) or exercise, which are safe and tolerable in humans, and our team is experienced and motivated. Neither the studies nor the interventions can be most effective without considering all aspects of the molecular bases of the disease, which is only possible in a highly interactive program such as that we propose here.