Recapitulation of sex- disparity in PAH on a microfluidic device and elucidation of the differences and similarities in the development, progression and therapy of PAH in male versus female patients

项目总结： 肺动脉高压(PAH)是一种致命的疾病，女性患病人数是男性的4倍。具有讽刺意味的是， 女性患者的情况比男性患者好；患有PAH的女性比男性患者多活两年。 患者对现有的PAH疗法的反应也因性别而异。PAH中的这些性别差异可能 至少部分源于两性之间的内在差异和性别角色的冲突 荷尔蒙，尤其是雌激素。雌激素促进肺血管平滑肌病理性增殖 但它也能预防右室肥厚(RVH)。男性荷尔蒙--睾酮的作用 对PAH的定义不明确，但它似乎在促进男性RVH方面起到了一定作用。对性行为的理解取得了进展- PAH的差异一直很缓慢，主要是因为缺乏能够概括人类的实验模型 多环芳烃的性别特有形式。现有的动物和细胞模型，同时帮助解决了许多重要的 问题，不能准确地描述多环芳烃的发展和进展中与性别相关的变异性，也不是 对某些机械研究有足够的延展性。一种多环芳烃的人体组织芯片模型--能够捕捉其性别-- 特定的疾病病因，复制PAH诱导的RVH，并模拟药物治疗的性别特异性反应- 可以在理解多环芳烃和铅的性别差异的机制方面提供亟需的突破 改善对PAH患者的治疗。最近，我们设计并制造了这样一种装置，一种最先进的装置 模拟肺动脉五层(血管周围、外膜、内侧、内膜)的微流控组织芯片 和流明)，无论是正常的还是患病的。此外，在初步研究中，我们证明了我们的组织芯片可以 重建受PAH影响的肺动脉，模拟疾病的严重性，并模拟 男性患者与女性患者的治疗反应。在这里，我们建议部署我们的新设备来研究 不同形式的PAH的病理生理学，研究性和性激素对发育和 疾病进展，并评估单一疗法和联合疗法在两性中的相对疗效。 我们还将修改芯片以重建PAH诱导的RVH，以研究细胞间通信是如何 心肌细胞和肺动脉细胞参与PAH的病理变化，并评价其对PAH的影响。 药物治疗PAH所致RVH。这是一个具有深远临床意义的特别创新的项目，因为它 结合微流控技术的力量和组合研究设计的灵活性来阐明 女性和男性PAH的发病机制。由一名药学科学家组成的调查小组 对多环芳烃有长期兴趣的一位化学工程师，一位微流控技术专家，两位医生 科学家和一位多环芳烃生物学家非常有资格进行这项研究。如果成功，这种组织芯片模型可能会 革新研究以性别为基础的病理生理学和血管疾病治疗的方法，并使 临床医生为他们的PAH患者开发个性化治疗。

Project Summary: Pulmonary arterial hypertension (PAH) is a lethal disease that affects ~4 times as many women as men. Ironically, female patients fare better than male patients; women with PAH live 2 years longer than their male counterparts. Patient responses to existing PAH therapies also vary depending on sex. These gender disparities in PAH may stem, at least in part, from intrinsic differences between the two sexes and from the conflicting roles of sex hormones, especially estrogen. Estrogen increases the pathologic proliferation of pulmonary arterial smooth muscle cells, but it also protects against right ventricular hypertrophy (RVH). The role of the male sex hormone testosterone in PAH is poorly defined but it appears to have a part in promoting RVH in men. Progress in understanding the sex- disparity in PAH has been slow, primarily because of the lack of experimental models that can recapitulate human PAH in its sex-specific forms. Existing animal and cellular models, while having aided in addressing many important questions, do not accurately portray the sex-related variability in PAH development and progression, nor are they sufficiently malleable for certain mechanistic studies. A human tissue-chip model of PAH—able to capture its sex- specific disease etiology, reproduce PAH-induced RVH, and simulate sex-specific responses to drug therapy— could provide a much-needed breakthrough in understanding the mechanism of the sex disparity in PAH and lead to improved treatments for PAH patients. Recently, we designed and fabricated such a device, a state-of-the-art microfluidic tissue-chip that mimics the five layers of the pulmonary artery (perivascular, adventitial, medial, intimal and luminal), both normal and diseased. Further, in preliminary studies, we demonstrated that our tissue-chip can recreate PAH-afflicted pulmonary arteries, emulate the severity of the disease, and model the differences in the therapeutic response of male versus female patients. Here, we propose to deploy our new device to study the pathophysiology of different forms of PAH, investigate the influence of sex and sex hormones on development and progression of the disease, and assess the relative efficacies of mono and combination therapies in both sexes. We will also modify the chip to reconstruct PAH-induced RVH to study how intercellular communication between cardiac cells and cells of PAH-afflicted pulmonary arteries contributes to the pathology, and evaluate the effect of drugs on PAH-induced RVH. This is an exceptionally innovative project with far-reaching clinical significance, as it combines the power of microfluidic technology with the flexibility of combinatorial study design to elucidate the pathomechanism of PAH in both women and men. The investigative team, comprising a pharmaceutical scientist with a longstanding interest in PAH, a chemical engineer, an expert in microfluidic technology, two physician scientists, and a PAH biologist, is highly qualified to conduct this study. If successful, this tissue-chip model may revolutionize approaches to studying sex-based pathophysiology and therapy for vascular diseases, and enable clinicians to develop personalized therapies for their PAH patients.