MICA: Interrogating the functional impact of novel asthma genetic variants using genomics and inducible pluripotent stem cell-derived epithelial cells

哮喘是一种影响肺部的常见疾病，会导致喘息、咳嗽和呼吸困难。它通常是轻微的，但症状的爆发会影响生活和工作的质量，在某些情况下可能是致命的。我们需要可靠和准确的方法来了解这种疾病的原因。目前，我们可以从哮喘患者的肺样本(活组织检查)中提取细胞，然后在实验室中培养进行研究。然而，由于采样产生的细胞数量很少，结果受到限制。在人类血液中发现的干细胞可以在人体内形成任何类型的细胞，新技术意味着我们可以从这些干细胞连续培养出“肺细胞”。我使用这些技术在我们的实验室中引导干细胞形成“肺细胞”，可以用来研究肺部疾病，如哮喘。哮喘部分是由遗传(遗传)风险因素引起的，这些因素是从父母那里遗传来的。哮喘的遗传原因一直很难研究，因为它是由许多不同的因素引起的。在过去的十年里，医生和科学家已经发现了一种新的哮喘亚型，被称为嗜酸性哮喘。这种哮喘的特征是我们的血液和呼吸中有某些标志物，可以很容易地用被称为“生物制剂”的新型注射药物来治疗。尽管这些药物非常有效，并改变了嗜酸性哮喘患者的生活，但我们仍然不完全了解是什么导致了这一亚型哮喘。我们也缺乏治疗其他形式哮喘的有效药物。我将继续我的工作，引导干细胞形成“肺细胞”，使这些肺细胞模仿哮喘患者的细胞。肺细胞将在不同的条件下培养，以模拟哮喘，并在实验的每个阶段进行检查，以确保我们制造的细胞类型正确。我将把我们的“肺细胞”的结构和功能与直接取自人类病人的肺细胞进行比较。“CRISPR/Cas9”是一种特殊的技术，我将用它来改变这些实验室“肺细胞”的基因组成，以更详细地研究遗传风险因素。血液样本将从患有独特和严重哮喘的家庭中提取，我将分析他们的基因序列，试图识别与特定哮喘亚型相关的DNA(遗传密码)变异。然后可以在我的“肺细胞”中更详细地研究基因变异(突变)，而不必从患者的肺部进行活组织检查。最重要的发现之一将是更详细地了解哮喘的一些遗传原因，特别是基因突变如何导致哮喘患者细胞的变化。这可能使我们能够在哮喘患者的特定部位找到新的药物靶点。我将在科学期刊上发表我的结果，并通过在科学会议上的陈述来讨论我的发现。这些信息将对其他科学家有用，他们正在开发预测哪些患者对特定治疗反应最好的方法。我是一名研究医生，接受过呼吸系统医学方面的培训，对遗传学和哮喘研究有兴趣和背景。支持我工作的研究团队将包括一名在哮喘研究方面具有专业知识的高级呼吸系统医生(顾问)和一名遗传学教授。我的研究将分为在实验室培养哮喘“肺细胞”和对哮喘患者家庭的遗传数据进行计算机分析。这是哮喘研究中一个及时而令人兴奋的领域，有可能回答有关哮喘病因的关键问题，并帮助患有这种疾病的严重形式的患者，这种疾病可能非常难以治疗。它还将通过展示这种尖端的、新的“肺细胞”技术如何在实验室改进我们的哮喘模型来帮助研究人员。

Asthma is a common disease affecting the lungs, which causes wheezing, coughing and difficulty breathing. It is usually mild but flares of symptom impact quality of life and work and can be fatal in some cases. We need reliable and accurate ways to understand what causes this disease. Currently, we can take lung samples (biopsies) from patients with asthma to provide cells, which are then grown in a laboratory to study. However, results are limited by the small number of cell generated from the involved sampling.Stem cells, found in human blood, can form any cell type in the body and new techniques mean we can continuously grow "lung cells" from these stem cells. I have used these techniques to direct stem cells in our laboratory to form "lung cells," which can be used to study lung diseases, such as asthma. Asthma is partly caused by genetic (hereditary) risk factors, which are inherited from our parents. The genetic causes of asthma have been difficult to study, as it is caused by many different factors. Over the last decade, doctors and scientists have recognised a new subtype of asthma known as 'eosinophilic asthma.' This form of asthma is characterised by certain markers in our blood and breath, and is easily treated with new injectable drugs called "biologics". Although these drugs work extremely well and have been life-changing for patients with eosinophilic asthma, we still do not fully understand what causes this subtype of asthma. We also lack effective medicines for other forms of asthma.I will continue my work directing stem cells to form "lung cells" and making these lung cells mimic cells in patients with asthma. The lung cells will be grown in different conditions to simulate asthma and checks performed at each stage of experiment to ensure we are making the right types of cells. I will compare the structure and function of our "lung cells" to lung cells taken directly from human patients. 'CRISPR/Cas9' is a special technique that I will use to change the genetic make-up of these laboratory "lung cells" to study hereditary risk factors in more detail. Blood samples will be taken from families with unique and severe forms of asthma and I will analyse their genetic sequences to try and identify variations in their DNA (hereditary code) that are associated with specific subtypes of asthma. The genetic variations (mutations) can then be studied in much greater detail in my "lung cells" without having to take biopsies from patient's lungs. One of the most important findings will be understanding some of the genetic causes of asthma in more detail, particularly how genetic mutations cause changes in the cells of patients with asthma. This may allow us to identify new drug targets in particular parts of "lung cells" in patients with asthma.I will publish my results in scientific journals and also discuss my findings through presentations at scientific meetings. Such information will be useful to other scientists developing ways of predicting which patients will respond best to specific treatments. I am a research doctor, training in respiratory medicine, with an interest and background in genetics as well as asthma research. The research team supporting my work will include a senior respiratory doctor (consultant) with expertise in asthma research and a professor of genetics. My research will be split between developing asthma "lung cells" in a laboratory and computer-based analysis of genetic data from families with asthma. This is a timely and exciting area in asthma research, which has the potential to answer key questions about the causes of asthma and help patients with severe forms of this disease, which can be extremely difficult to treat. It will also help researchers by demonstrating how this cutting-edge, new "lung cell" technique can improve our asthma models in laboratories.