Mechanobiology of Cardiopulmonary Fibrosis

摘要 心肺纤维化是多种病理的统一因素，包括心肌梗死后 导致心力衰竭、心脏瓣膜病(HVD)和肺脏的心肌梗死(MI)疤痕形成 动脉高血压(PAH)等。我的实验室探索成纤维细胞驱动的 心肺纤维化重塑的力学生物学机制及其研究进展 预防或治疗这些疾病的策略。我们的重点是心肺成纤维细胞以及如何 他们独特的表型特征可以被用来阻止他们的纤维化机制。我们独一无二 利用我们的工程专业知识解决机械生物输入问题 心肺纤维化，通过有效地结合疾病的动物模型和原代细胞 体外研究。我们以前的成就为未来桥接钥匙的承诺提供了强有力的证据 我们在认识上的差距导致了新的治疗策略的发展。最初，我们 重点是HVD，但后来扩展到包括PAH在内的全身性心肺纤维化， 这会导致右心衰竭和心肌梗塞后的纤维化。这些新的追求是 补充我们在HVD方面成熟的研究计划，并结合我的实验室 NHLBI研究组合将使我们能够取得快速进展，并将我们的发现转化为 患者：1)在过去成就的基础上，同时保持目前的努力和 足够灵活地抓住研究活动过程中出现的机会；2)巩固 心肺机械生物学的价值和定位我的团队不仅要继续我们的 研究，但在NHLBI社区更广泛地“播种”专业知识；3)最大限度地利用共同 更有效地使用昂贵的试剂和动物模型；4)支持我的八国集团 受训人员处于稳定状态，包括两名初级教员。

Summary Cardiopulmonary fibrosis is a unifying factor in multiple pathologies, including post myocardial infarction (MI) scarring that leads to heart failure, heart valve disease (HVD), and pulmonary arterial hypertension (PAH), among others. My laboratory explores fibroblast-driven, mechanobiological mechanisms of cardiopulmonary fibrotic remodeling and develops innovative strategies to prevent or treat these diseases. We focus on cardiopulmonary fibroblasts and how their unique phenotypic signatures can be targeted to halt their fibrotic machinery. We uniquely leverage our engineering expertise to address mechanobiological inputs that drive cardiopulmonary fibrosis, by effectively combining animal models of disease with primary cell in vitro studies. Our prior accomplishments provide strong evidence for future promise to bridge key gaps in our understanding that leads to development of novel treatment strategies. Initially, we focused on HVD, but have since expanded into general cardiopulmonary fibrosis, including PAH, which results in right heart failure, and fibrosis following MI. These new pursuits are complementary to our well-established research program in HVD and combining my laboratory’s NHLBI research portfolio would allow us to make rapid progress and translate our findings to patients by: 1) building on past accomplishments, while sustaining present efforts and being nimble enough to pursue opportunities presented in the course of research activities; 2) solidifying the value of cardiopulmonary mechanobiology and positioning my group to not only continue our research but to “seed” expertise more broadly in the NHLBI community; 3) maximizing common use of costly reagents and animal models more effectively; 4) supporting my group of eight trainees at steady state, including two junior faculty.