Investigation of REVERBalpha as a therapeutic target in pulmonary fibrosis

REVERBalpha 作为肺纤维化治疗靶点的研究

• 批准号: MR/L006499/1
• 负责人: John Blaikley
• 金额: $ 131.49万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL006499%2F1
• 关键词: Investigation; REVERBalpha; therapeutic; target; pulmonary

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.

特发性肺纤维化(IPF)是一种肺部疾病，在英国每年导致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，我发现了一种新的方法来调节它们。正常情况下，肌成纤维细胞不存在于健康组织中，但在损伤后会出现。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。肌成纤维细胞在特发性肺间质纤维化中的重要性从患者活检组织中观察到的这些细胞的病理性堆积中可见一斑。因此，一个有吸引力的治疗方法将是抑制肌成纤维细胞的发展，以及它们的功能可能阻止疾病的进展并允许愈合。我发现一种重要的细胞调节蛋白，REVERBalpha，可以防止正常、健康的肺细胞形成肌成纤维细胞。我现在想推动这一令人兴奋的发展，以确定靶向REVERBalpha是否是患者可行的治疗选择，有可能提供一种挽救生命的治疗方法。REVERBalpha属于一种名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器，目标是储存或利用它们。在我之前的MRC赞助的研究中，我开发了改变REVERBalpha功能的新化合物。我证明了这些化合物可以调节人类肺炎性细胞的功能。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可以阻止肌成纤维细胞的发育。我提出的研究将探讨REVERBalpha在肺纤维化中的作用。首先，我将在人类纤维性肺疾病模型中研究REVERBalpha的缺失如何影响肺纤维化的发展。然后我将测试我的新奇的“类药物”小分子如何防止纤维化的发展。我已经开发了新的资源来允许这一领域的快速进展，包括一种新的抗体，它可以精确测量肺纤维化患者的REVERBalpha蛋白水平，并与正常的健康肺组织进行比较。我还发现REVERBalpha可以改变细胞管理其能量需求的方式，导致一些小分子的明显变化，包括一些类型的脂肪，统称为代谢物。这与IPF非常相关，因为我也证明了其中一些肺代谢产物可以改变肌成纤维细胞的分化。因此，我计划对同一患者健康和患病肺部的代谢物进行采样；这将使我能够确定IPF引起的代谢变化。然后，我可以选择调查候选代谢物，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的哪些基因是REVERBalpha的目标，包括调控是如何管理的，以及对细胞的影响是什么。这将确定新的途径和额外的药物靶点，以便在目前的研究基础上进行进一步研究。我已经召集了一个国际合作的研究人员来解决这个新的假设，它提供了额外的好处，为我提供了一次极好的研究培训体验。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和多伦多的研究人员也将参与其中，包括基础科学家和临床研究人员。总而言之，我将探索一种潜在的治疗方案，以治疗一种日益常见和致命的肺部疾病，目前尚无有效的治疗方法。

项目成果

The circadian clock protein REVERBa inhibits pulmonary fibrosis development

生物钟蛋白 REVERBa 抑制肺纤维化发展

• DOI: 10.1101/781666
• 发表时间: 2019
• 作者: Cunningham P

Additive anti-inflammatory effects of corticosteroids and phosphodiesterase-4 inhibitors in COPD CD8 cells.

• DOI: 10.1186/s12931-016-0325-8
• 发表时间: 2016-01-25
• 期刊: Respiratory research
• 影响因子: 5.8
• 作者: Grundy S;Plumb J;Kaur M;Ray D;Singh D
• 通讯作者: Singh D

Reply to Moitra et al. : Individual Chronotype May Confound Asthma Symptoms and Therapy

回复莫伊特拉等人。

• DOI: 10.1164/rccm.201809-1712le
• 发表时间: 2019
• 期刊: American Journal of Respiratory and Critical Care Medicine
• 影响因子: 24.7
• 作者: Durrington H