Mechanosignaling regulates macrophage immunometabolism

项目摘要 肺纤维化是一类以亚急性和慢性进行性瘢痕形成为特征的疾病 肺的。最常见的形式是特发性肺纤维化（IPF），在200名患者中患病率为1/200。 65岁以上的人。IPF是一种破坏性疾病，中位生存期为3 - 5年， 停止其进展。最近的研究强调了巨噬细胞，特别是单核细胞的关键作用， 衍生的巨噬细胞（MDM），在肺纤维化。巨噬细胞具有高度可塑性， 在纤维化过程中的重编程和交替激活。巨噬细胞及其纤维化的相互作用 环境对纤维化进展至关重要。许多研究表明，不同的生化 信号可以诱导巨噬细胞代谢重编程和替代激活;然而， 可用于证明是否物理信号，如增强的细胞外基质（ECM）硬度， 肺纤维化过程中的主要变化，可以调节巨噬细胞代谢重编程和替代 activation.我们的初步数据显示，巨噬细胞在基质上培养， 肺（20 kPa）与在柔软柔顺基质上培养的巨噬细胞相比， 硬度与正常健康肺相似（0.5 kPa）。整合素β3在人肺巨噬细胞中的表达 肺纤维化受试者和实验性纤维化动物。从机制上讲，我们假设 巨噬细胞利用整合素β3作为机械传感器激活过氧化物酶体增殖物激活受体γ来调节代谢 重编程和替代激活。在目标1中，我们将确定ECM刚度是否调节巨噬细胞 代谢重编程在目标2中，我们将确定巨噬细胞利用的机械信号通路， 来调节代谢重编程在目标3中，我们将在实验肺中测试我们的假设。 纤维化小鼠模型，以确定是否中断PPARγ介导的机械信号传导和代谢 巨噬细胞中的重编程可以减轻体内肺纤维化。通过完成这项拟议的研究， 我们的目的是表明1）巨噬细胞通过整合素αvβ3感知ECM刚度; 2）基质刚度可以调节 3）PPARγ是一种机械敏感性转录因子， 抑制巨噬细胞αvβ3-过氧化物酶体增殖物激活受体γ机械传导通路， 体内纤维化。我将利用这一建议，以获得额外的技能，在尖端领域的机械， 免疫代谢组学通过一系列的教学和应用培训下的导师， 经验丰富的多学科团队。这个K 08将有助于我过渡到一个独立的物理学家，科学家 研究肺纤维化的发病机制，具有独特的机械免疫研究生态位， 代谢组学这项研究计划还将有助于确定新的机制和治疗目标， 肺纤维化，这是致命的，治疗有限。

PROJECT SUMMARY Pulmonary fibrosis is a class of disease conditions characterized by subacute and chronic progressive scarring of the lungs. The most common form, idiopathic pulmonary fibrosis (IPF), has a prevalence of 1 in 200 among people older than 65. IPF is a devastating disease with a median survival of 3 to 5 years with limited therapy to halt its progression. Recent research had highlighted the critical role of macrophages, particularly monocyte- derived macrophages (MDMs), in pulmonary fibrosis. Macrophages are highly plastic and undergo metabolic reprogramming and alternative activation during fibrosis. The interactions of macrophages and their fibrotic environment are crucial for fibrosis progression. Numerous studies have shown that different biochemical signals can induce macrophage metabolic reprogramming and alternative activation; however, limited data are available to demonstrate whether physical signals such as enhanced extracellular matrix (ECM) stiffness, the cardinal changes during lung fibrosis, can modulate macrophage metabolic reprogramming and alternative activation. Our preliminary data showed that macrophages cultured on matrix with stiffness similar to fibrotic lungs (20 kPa) had increased PPARγ compared to macrophages cultured on a soft and compliant matrix with stiffness similar to normal health lungs (0.5 kPa). Integrin β3 is increased in lung macrophages from human subjects with pulmonary fibrosis and animal with experimental fibrosis. Mechanistically, we hypothesize that macrophages utilize integrin β3 as the mechanosensor to activate PPARγ to modulate metabolic reprogramming and alternative activation. In Aim 1, we will determine if ECM-stiffness regulates macrophage metabolic reprogramming. In Aim 2, we will determine the mechanosignaling pathway utilized by macrophages to modulate metabolic reprogramming. In Aim 3, we will test our hypothesis in an experimental pulmonary fibrosis mice model to determine whether interrupting PPARγ-mediated mechanosignaling and metabolic reprogramming in macrophages can attenuate pulmonary fibrosis in vivo. By completing this proposed study, we aim to show that 1) macrophages sense ECM stiffness via Integrin αvβ3; 2) matrix stiffness can modulate macrophage metabolism to sustain its alternative activation; 3) PPARγ is a mechanosensitive transcription factor, and 4) inhibiting αvβ3-PPARγ mechanotransduction pathway in macrophages can attenuate pulmonary fibrosis in vivo. I will utilize this proposal to acquire additional skills in the cutting-edge field of mechano- immuno-metabolomics through a series of didactic and applied training under the mentorship of an experienced multidisciplinary team. This K08 will facilitate my transition to an independent physician-scientist studying the pathogenesis of pulmonary fibrosis, with a unique research niche of mechano-immuno- metabolomics. This research proposal will also aid in identifying novel mechanisms and targets for therapies in pulmonary fibrosis, which is fatal and with limited treatment.