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

这个奖学金将跳板我的学术生涯的重新启动后，从行业过渡，使我能够开发一个创新的工作计划，建立研究势头，并把肺领域的分子表观遗传学的一个新领域。因此，它将使我成为新兴的肺表观遗传学领域的研究领导者。慢性肺部疾病是我们这一代最紧迫的医疗挑战之一，有5.4亿患者等待治愈治疗。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。我的研究为肺部领域带来了独特的表观遗传视角，其总体目标是在肺组织发生不可逆变化之前在发病时对抗肺部疾病。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。在这个项目中，我将利用我在表观遗传学和肺生物学方面的独特专长，来确定健康个体如何发展为肺纤维化，并为未来的药物开发确定新的靶点。特发性肺纤维化（IPF）是一种无法治愈的肺部疾病，患者由于肺部不可逆的瘢痕而经历进展性呼吸困难。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。三个特征促成了这一严峻的现实：1）IPF原因未知，限制了预防的可能性2）诊断具有挑战性，因为没有早期检测的工具3）治疗有限，具有严重的副作用，无法治愈。为了发现新的诊断和治疗方案，需要精确了解驱动疾病的分子变化。我们知道，表观遗传机制控制着我们的基因如何以及何时打开或关闭。我们还知道，表观遗传标记可以通过环境暴露而改变，从而导致疾病。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，表观遗传信号提供了一个新的独特的角度来理解疾病如何开始，什么变化驱动其进展。然而，尽管在IPF中发现了一些表观遗传变化，但尚未对IPF中的表观遗传失调进行全面分析。在这个项目中，我将采用一种无偏的分析方法来比较健康和IPF细胞在疾病各个阶段的表观遗传特征，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，以确定和验证用于疾病检测的新候选标志物。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，并研究它们的功能相关性。通过这种开创性的方法，我将确定哪些位点可能在疾病中起因果作用，为干预提供最有希望的靶点。最后，我将利用这些知识来识别新的疾病调节剂。我在临床前药物开发和剖析疾病的表观遗传机制方面具有跨部门的经验，因此能够实现这个雄心勃勃的项目。但这个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表观遗传学研究的方式，使未来的科学家和患者受益，并使我成为这一新兴研究领域的领导者。该奖学金还将使威尔士和英国更广泛的社区参与呼吸健康，创造真实的科学，经济和社会影响。

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.