Uncovering the epigenetic face of lung fibrosis for discovery of novel biomarkers and treatments.

揭示肺纤维化的表观遗传面，以发现新的生物标志物和治疗方法。

• 批准号: MR/X032914/1
• 负责人: Renata Jurkowska
• 金额: $ 202.81万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX032914%2F1
• 关键词: Uncovering; epigenetic; face; lung; fibrosis

This fellowship will springboard the restart of my academic career after transitioning from industry, enabling me to develop an innovative program of work, build the research momentum and bring the lung field into a new area of molecular epigenetics. Thus, it will enable my establishment as a research leader in the emerging field of lung epigenetics.Chronic lung diseases are one of the most pressing healthcare challenges of our generation, with 540 million patients waiting for curative treatments. Thus, we urgently need innovative and interdisciplinary approaches to address this global challenge. My research brings a unique epigenetic perspective to the lung field with the overarching aim to combat lung diseases at their onset before irreversible changes in the lung tissue occur. The link between lung diseases, environmental exposures and epigenetics is well established, however, how epigenetic changes drive lung disease development is unknown. Likewise, it remains unclear whether epigenetic mechanisms can be targeted for the development of novel therapeutic approaches for lung diseases. In this fellowship, I will capitalise on my unique combination of expertise in epigenetics and lung biology to determine how healthy individuals progress to develop lung fibrosis and identify novel targets for future drug development.Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease, where patients experience progressing breathing difficulties due to irreversible scarring of their lungs. 5 million people worldwide currently live with IPF, having a poor quality of life and an average survival of 3 years after diagnosis. Three features contribute to this grim reality: 1) IPF causes are unknown, limiting possibilities for prevention 2) diagnosis is challenging as no tools for early detection are available 3) treatments are limited, have severe side effects and offer no cure. For discovery of novel diagnostic and treatment options, a precise understanding of molecular changes driving disease is required.We know that epigenetic mechanisms control how and when our genes are switched on or off. We also know that epigenetic marks can be altered by environmental exposures causing disease. Excitingly, epigenetic marks can also be manipulated with the potential to cure disease. Thus, epigenetic signalling provides a novel unique angle for understanding how the disease starts and what changes drive its progression. Yet, despite the discovery of some epigenetic changes in IPF, the comprehensive profiling of epigenetic dysregulation in IPF has not been undertaken. In this project, I will employ an unbiased profiling approach to compare global epigenetic signatures of healthy and IPF cells across disease stages and discover epigenetic changes characteristic of early and late disease. I will interrogate the molecular signature of IPF to identify and validate novel candidate markers for disease detection. Importantly, I will then apply our unique epigenetic editing approaches in cell culture to specifically reverse aberrant epigenetic changes and examine their functional relevance. Through this pioneering approach, I will determine which sites may play a causal role in disease, providing the most promising targets for interventions. Finally, I will harness this knowledge to identify novel disease regulators.I am uniquely placed to deliver this ambitious project as I have cross-sector experience in preclinical drug development and in dissecting epigenetic mechanisms of disease. But this fellowship is more than just a scientific project. My unique approach has the potential to transform the way lung epigenetic research is done, benefiting future generations of scientists and patients, and establishing me as a leader in this emerging research field. This fellowship will also enable engagement of the wider community in Wales and UK around respiratory health, creating a real scientific, economic, and social impact.

这项奖学金将成为我从工业界转型后重新开始学术生涯的跳板，使我能够制定创新的工作计划，建立研究动力，并将肺领域带入分子表观遗传学的新领域。因此，这将使我成为新兴的肺表观遗传学领域的研究领导者。慢性肺病是我们这一代最紧迫的医疗挑战之一，有 5.4 亿患者正在等待治疗。因此，我们迫切需要创新和跨学科的方法来应对这一全球挑战。我的研究为肺领域带来了独特的表观遗传学视角，总体目标是在肺组织发生不可逆转的变化之前对抗肺部疾病。肺部疾病、环境暴露和表观遗传学之间的联系已得到充分证实，然而，表观遗传学变化如何驱动肺部疾病的发展尚不清楚。同样，目前还不清楚表观遗传机制是否可以作为开发肺部疾病新治疗方法的目标。在这项研究金中，我将利用我在表观遗传学和肺部生物学方面的专业知识的独特组合，确定健康个体如何进展为肺纤维化，并确定未来药物开发的新靶标。特发性肺纤维化（IPF）是一种无法治愈的肺部疾病，其中由于肺部不可逆转的疤痕，患者会出现呼吸困难的情况。目前全球有 500 万人患有 IPF，生活质量差，诊断后平均生存期为 3 年。三个特征导致了这一严峻的现实：1) IPF 原因未知，限制了预防的可能性 2) 诊断具有挑战性，因为没有可用的早期检测工具 3) 治疗方法有限，具有严重的副作用并且无法治愈。为了发现新的诊断和治疗方案，需要精确了解导致疾病的分子变化。我们知道表观遗传机制控制我们的基因打开或关闭的方式和时间。我们还知道，表观遗传标记可能会因导致疾病的环境暴露而改变。令人兴奋的是，表观遗传标记也可以被操纵，具有治愈疾病的潜力。因此，表观遗传信号为了解疾病如何发生以及哪些变化驱动其进展提供了一个新颖独特的角度。然而，尽管发现了 IPF 的一些表观遗传变化，但尚未对 IPF 的表观遗传失调进行全面分析。在这个项目中，我将采用公正的分析方法来比较健康细胞和 IPF 细胞在疾病阶段的整体表观遗传特征，并发现早期和晚期疾病的表观遗传变化特征。我将研究 IPF 的分子特征，以识别和验证用于疾病检测的新型候选标记。重要的是，我将在细胞培养中应用我们独特的表观遗传编辑方法，以特异性逆转异常的表观遗传变化并检查其功能相关性。通过这种开创性的方法，我将确定哪些位点可能在疾病中发挥因果作用，从而提供最有希望的干预目标。最后，我将利用这些知识来识别新的疾病调节因子。我在临床前药物开发和剖析疾病表观遗传机制方面拥有跨部门经验，因此我处于独特的地位来完成这个雄心勃勃的项目。但这项奖学金不仅仅是一个科学项目。我独特的方法有可能改变肺部表观遗传学研究的方式，使后代科学家和患者受益，并使我成为这个新兴研究领域的领导者。该奖学金还将促进威尔士和英国更广泛的社区参与呼吸健康问题，产生真正的科学、经济和社会影响。