Investigation of REVERBalpha as a therapeutic target in pulmonary fibrosis

特发性肺纤维化（IPF）是一种肺部疾病，在英国每年有5000人死亡，几乎没有有效的治疗方法。肌成纤维细胞是IPF中的一种关键细胞类型，我发现了一种调节它们的新方法。肌成纤维细胞通常不存在于健康组织中，但在损伤时发生。这种发育/分化部分受上皮细胞或巨噬细胞分泌的关键信使的控制。肌成纤维细胞在IPF中的重要性通过在来自患者的活检中观察到的这些细胞的病理学积累来显示。因此，一种有吸引力的治疗方法将是抑制肌成纤维细胞的发育，以及它们潜在地阻止疾病进展并允许愈合的功能。我发现一种重要的细胞调节蛋白REVERBalpha可以阻止正常健康肺细胞形成肌成纤维细胞。我现在想把这一令人兴奋的进展向前推进，以确定靶向REVERBalpha是否是患者的可行治疗选择，可能提供挽救生命的治疗。REVERB α属于一个称为核激素受体的蛋白质家族。REVERBalpha是身体处理饮食中脂肪的能力的主要调节剂，针对它们进行储存或利用。在我以前的MRC资助的研究中，我开发了改变REVERB α功能的新化合物。我证明了这些化合物可以调节人类肺部炎症细胞的功能。我现在已经扩展了这些发现，并表明这些化合物在实验室中阻止了肌成纤维细胞的发育。我计划的研究将探讨REVERB α在肺纤维化中的作用。首先，我将在人类纤维化肺病模型中研究REVERB α的缺失如何影响肺纤维化的发展。然后，我将测试我的新型“药物样”小分子如何预防纤维化发展。我开发了新的资源来实现这一领域的快速进展，包括一种新的抗体，可以精确测量肺纤维化患者的REVERB alpha蛋白水平，与正常、健康的肺组织进行比较。我还发现REVERB alpha可以改变细胞管理能量需求的方式，导致许多小分子发生明显变化，包括某些类型的脂肪，统称为代谢物。这与IPF非常相关，因为我还证明了这些肺部代谢物中的一些可以改变肌成纤维细胞的分化。因此，我计划在同一患者的健康和患病肺部采集代谢物样本;这将使我能够识别IPF引起的代谢变化。然后，我可以选择研究候选代谢物，目的是发现哪些代谢物受REVERBalpha调节，并在疾病进展中发挥致病作用。最后，我将应用新技术来研究肺细胞中哪些基因是REVERBalpha的靶点，包括如何管理调节以及对细胞的影响。这将确定新的途径和额外的药物靶点，以便在目前的奖学金之外进行进一步的研究。我已经召集了一个国际研究人员合作来解决这个新的假设，它通过为我提供一流的研究培训经验而提供了额外的好处。虽然这项研究将主要在曼彻斯特进行，但来自英国其他地区的研究人员，包括基础科学家和临床研究人员，以及多伦多也将参与其中。总之，我将探索一种潜在的治疗方案，用于治疗一种日益常见和致命的肺部疾病，目前还没有有效的治疗方法。

Idiopathic pulmonary fibrosis (IPF) is a lung disease that kills 5000 people a year in the UK with few effective treatments. Myofibroblasts are a key cell type in IPF, and I have discovered a new way to regulate them. Myofibroblasts are not normally found in healthy tissue but occur in response to injury. This development/ differentiation is partly under the control of key messengers secreted by epithelial cells or macrophages. The importance of myofibroblasts in IPF is shown by the pathological accumulation of these cells observed in biopsies from patients. Therefore an attractive treatment approach would be to inhibit the development of myofibroblasts, and their function potentially stopping disease progression and permit healing. I have discovered that an important cell regulator protein, REVERBalpha, can prevent the formation of myofibroblasts from normal, healthy lung cells. I now want to take this exciting development forward, to determine if targeting REVERBalpha is a viable treatment option for patients, potentially providing a life saving treatment. REVERBalpha belongs to a family of proteins called nuclear hormone receptors. REVERBalpha is a master regulator of the body's capacity to handle fats from the diet, targeting them for storage, or utilisation. In my previous MRC sponsored research I developed novel compounds that alter the function of REVERBalpha. I showed that these compounds can regulate the function of inflammatory cells from the human lung. I have now extended these findings and shown that these compounds stop the development of myofibroblasts in the lab. My proposed research will investigate the function of REVERBalpha in lung fibrosis. Initially I will examine how loss of REVERBalpha affects development of lung fibrosis in models of human fibrotic lung disease. I will then test how my novel "drug-like" small molecules can prevent fibrosis development. I have developed new resources to permit rapid progress in this area, including a new antibody which permits precise measurement of REVERBalpha protein levels in patients with lung fibrosis, comparing against normal, healthy lung tissue.I have also discovered that REVERBalpha can alter how cells manage their energy requirements, leading to distinct changes in a number of small molecules, including some types of fat, together termed metabolites. This is very relevant for IPF as I have also shown that some of these pulmonary metabolites can alter the differentiation of myofibroblasts. I therefore plan to sample metabolites in both healthy and diseased lungs in the same patient; this will allow me to identify metabolic changes caused by IPF. I then have the option of investigating candidate metabolites with the aim of discovering which are regulated by REVERBalpha and play a causative role in disease progression. Finally, I will apply new technology to investigate which genes in the lung cells are targets for REVERBalpha including how the regulation is managed and what the consequences are for the cell. This will identify new pathways and additional drug targets for further studies beyond the current fellowship. I have brought together an international collaboration of researchers to address this novel hypothesis, which provides added benefit by offering me a superb research training experience. Though the research will be mainly conducted in Manchester, researchers, both basic scientists and clinical investigators, from other parts of the U.K. as well as Toronto will also be involved. In summary, I will be exploring a potential treatment option for an increasingly common and fatal lung disease for which no effective treatments currently exist.