PI3K Signaling and Aberrant Neutrophil Function in COPD; Implications for Disease Susceptibility, Prognosis and Therapeutic Targeting

COPD 中的 PI3K 信号传导和中性粒细胞功能异常；

• 批准号: MR/L008335/1
• 负责人: Elizabeth Sapey
• 金额: $ 29.5万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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%2FL008335%2F1
• 关键词: PI3K; Signaling; Aberrant; Neutrophil; Function

Chronic Obstructive Pulmonary Disease (COPD) is a term that describes conditions such as emphysema and chronic bronchitis which are characterised by narrowing of the breathing tubes (airways), and are associated with lung tissue destruction. It is debilitating, affects 3 million people in the UK, and is the 5th leading cause of death (25,000 deaths in the UK/year). It is the only chronic disease with a rising death rate. UK COPD costs are estimated at £3.2 billion per annum. Annual NHS costs are £900M, 50% of which are due to unscheduled hospital admissions due to deteriorating symptoms. Better disease management would reduce this disease burden, but currently no treatments prevent disease onset or halt progression. COPD is a chronic inflammatory condition, where the continued presence of excessive inflammatory proteins and cells in the lung cause damage. Smoking cigarettes is the most important risk factor, but only 15% of smokers develop COPD, and the disease runs in families, suggesting there are genetic factors that predispose towards COPD. Inflammation and lung destruction continue even after smoking cessation. This is poorly understood, but we believe that COPD patients have abnormal immune responses that drive disease even after noxious stimuli (cigarette smoke) have gone. Presently we cannot predict who will develop COPD or if all disease features are caused by the same underlying immune problem. It is vital to understand this, as it will help direct new treatments.Neutrophils are white blood cells crucial for fighting infection. They leave the blood, moving (migrating) accurately to areas of infection, where they ingest bacteria, killing them with an arsenal of proteins contained within the cell. These proteins cause damage and inflammation if they are released in the body's tissues. Neutrophils contain genes that control the cell by dictating what proteins are expressed. These proteins could be enzymes, controlling chemical reactions within the neutrophil, or structural proteins, controlling how they move. Neutrophils are central to COPD. COPD patients have many neutrophils in their lungs and the chemicals neutrophils release can cause the characteristic lung damage. Our data show that neutrophils from COPD patients are defective, migrating less accurately than cells from healthy subjects or people with other lung diseases and ingest less bacteria in models of infection. This is important, as inaccurate migration and reduced bacterial clearance could lead to more lung damage and poorer outcomes during infections; both of these are thought central in COPD. We have shown this harmful cell behaviour is due to increased activity of a protein enzyme called phophosinositide-3 kinase (PI3K). Abnormal PI3K signalling may be the cause of altered COPD neutrophil behaviour and correcting this may offer a new treatment in COPD.We wish to investigate the molecular signals and identify the relevance of injurious neutrophil behaviour in COPD, using neutrophils isolated from blood and lung secretions of COPD patients, those at risk of developing COPD (family members of COPD patients) and healthy volunteers. This will determine how prevalent the defective neutrophil behaviour is across all the differing features of COPD, and whether you can predict who might develop the disease by assessing their neutrophils. We will then identify the cause of the defective neutrophil behaviour, by studying the activity of structural proteins and enzymes (and the genes that control them) within COPD neutrophils, using our extensive preliminary data and knowledge of cell signaling to focus our experiments. Identifying the specific cause of defective neutrophil behaviour will allow us to form new targeted treatments for COPD, improving the health of patients with the disease. It may also allow us to predict who is most at risk of the COPD, developing a screening tool, helping to inform people about their lifestyle choices.

慢性阻塞性肺疾病（COPD）是一个描述肺气肿和慢性支气管炎等疾病的术语，其特征是呼吸管（气道）变窄，并与肺组织破坏有关。它使人衰弱，在英国影响300万人，是第五大死亡原因（英国每年有25,000人死亡）。它是唯一一种死亡率不断上升的慢性病。据估计，英国每年的慢性阻塞性肺病费用为32亿英镑。NHS每年的费用为9亿英镑，其中50%是由于症状恶化而导致的计划外住院。更好的疾病管理将减轻这种疾病负担，但目前没有任何治疗方法可以预防疾病发作或阻止疾病进展。慢性阻塞性肺病是一种慢性炎症，肺部持续存在过多的炎症蛋白和细胞会导致损伤。吸烟是最重要的风险因素，但只有15%的吸烟者会患上慢性阻塞性肺病，而且这种疾病是家族遗传的，这表明有遗传因素易导致慢性阻塞性肺病。即使在戒烟后，炎症和肺部损害仍在继续。这一点尚不清楚，但我们认为COPD患者有异常的免疫反应，即使在有害刺激（香烟烟雾）消失后也会导致疾病。目前我们无法预测谁会发展为慢性阻塞性肺病，也无法预测是否所有的疾病特征都是由相同的潜在免疫问题引起的。了解这一点至关重要，因为它将有助于指导新的治疗方法。中性粒细胞是对抗感染的关键白血球。它们离开血液，准确地移动（迁移）到感染区域，在那里它们摄入细菌，用细胞内的蛋白质库杀死细菌。如果这些蛋白质被释放到身体组织中，就会造成损伤和炎症。中性粒细胞含有通过决定表达什么蛋白质来控制细胞的基因。这些蛋白质可能是控制中性粒细胞内化学反应的酶，也可能是控制它们如何移动的结构蛋白。中性粒细胞是慢性阻塞性肺病的核心。慢性阻塞性肺病患者的肺部有许多中性粒细胞，中性粒细胞释放的化学物质会引起特征性的肺损伤。我们的数据显示，在感染模型中，来自COPD患者的中性粒细胞存在缺陷，迁移的准确性低于健康受试者或其他肺部疾病患者的细胞，并且摄入的细菌更少。这一点很重要，因为不准确的迁移和细菌清除减少可能导致更多的肺损伤和感染期间较差的结果；这两种都被认为是慢性阻塞性肺病的核心。我们已经证明，这种有害的细胞行为是由于一种叫做磷酸苷酸-3激酶（PI3K）的蛋白质酶的活性增加。异常的PI3K信号可能是导致COPD中性粒细胞行为改变的原因，纠正这一点可能为COPD提供一种新的治疗方法。我们希望通过从COPD患者、COPD风险患者（COPD患者家属）和健康志愿者的血液和肺分泌物中分离出的中性粒细胞，研究分子信号并确定COPD中有害中性粒细胞行为的相关性。这将决定有缺陷的中性粒细胞行为在COPD的所有不同特征中有多普遍，以及你是否可以通过评估他们的中性粒细胞来预测谁可能患上这种疾病。然后，我们将通过研究慢性阻塞性肺病中性粒细胞中的结构蛋白和酶（以及控制它们的基因）的活性，利用我们广泛的初步数据和细胞信号传导知识来确定中性粒细胞行为缺陷的原因。确定中性粒细胞行为缺陷的具体原因将使我们能够形成针对慢性阻塞性肺病的新靶向治疗方法，改善该疾病患者的健康状况。它还可以让我们预测谁最有可能患慢性阻塞性肺病，开发一种筛查工具，帮助人们了解他们的生活方式选择。

项目成果

Symptoms, complications and management of long COVID: a review.

• DOI: 10.1177/01410768211032850
• 发表时间: 2021-09
• 期刊: Journal of the Royal Society of Medicine
• 影响因子: 17.3
• 作者: Aiyegbusi OL;Hughes SE;Turner G;Rivera SC;McMullan C;Chandan JS;Haroon S;Price G;Davies EH;Nirantharakumar K;Sapey E;Calvert MJ;TLC Study Group
• 通讯作者: TLC Study Group

Perceptions of anonymised data use and awareness of the NHS data opt-out amongst patients, carers and healthcare staff.

• DOI: 10.1186/s40900-021-00281-2
• 发表时间: 2021-06-14
• 期刊: Research involvement and engagement
• 作者: Atkin C;Crosby B;Dunn K;Price G;Marston E;Crawford C;O'Hara M;Morgan C;Levermore M;Gallier S;Modhwadia S;Attwood J;Perks S;Denniston AK;Gkoutos G;Dormer R;Rosser A;Ignatowicz A;Fanning H;Sapey E;PIONEER Data Hub
• 通讯作者: PIONEER Data Hub

Development and external validation of prognostic models for COVID-19 to support risk stratification in secondary care.

• DOI: 10.1136/bmjopen-2021-049506
• 发表时间: 2022-01-17
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Adderley NJ;Taverner T;Price MJ;Sainsbury C;Greenwood D;Chandan JS;Takwoingi Y;Haniffa R;Hosier I;Welch C;Parekh D;Gallier S;Gokhale K;Denniston AK;Sapey E;Nirantharakumar K
• 通讯作者: Nirantharakumar K

The changing characteristics of COVID-19 presentations: A regional comparison of SARS-CoV-2 hospitalised patients during the first and second wave

COVID-19 表现的变化特征：第一波和第二波期间 SARS-CoV-2 住院患者的区域比较

• DOI: 10.1101/2021.02.07.21251297
• 发表时间: 2021
• 作者: Atkin C

A Systematic Review of the Use of Physiological Tests Assessing the Acute Response to Treatment During Exacerbations of COPD (with a Focus on Small Airway Function).

系统评价使用生理测试评估 COPD 恶化期间对治疗的急性反应（重点关注小气道功能）。

• DOI: 10.1080/15412555.2020.1815183
• 发表时间: 2020
• 期刊: COPD
• 影响因子: 2.2
• 作者: Alobaidi NY