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

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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.