Inflammasome complex organisation in infectious and inflammatory diseases

炎症可以保护人们免受感染，但它可能被过度激活，例如在败血症或无菌炎症中，它会导致严重的疾病。2017年，败血症造成的死亡人数占全球总死亡人数的20%，但COVID-19引起的严重疾病显著增加了这一死亡人数。无菌炎症是关节炎、II型糖尿病、癌症、慢性呼吸道疾病、动脉粥样硬化、阿尔茨海默病和帕金森病等疾病的基础，全球负担日益沉重。在英国，超过2000万人患有关节炎，大约85万人患有痴呆症，每年花费260亿英镑，预计到2051年病例将达到200万。全球有5.45亿人患有慢性呼吸道疾病。目前急需开发治疗败血症和慢性炎症的新药，因为现有的药物要么效率不高，要么有严重的副作用。存在于细胞内的受体（nod样受体（NLRs））感知病原体或无菌炎症刺激，形成一种称为炎性体的复合物，最终杀死细胞。炎性小体复合物是驱动炎症的关键，所以为了开发更好的抗炎疗法，有必要了解炎性小体复合物是如何在细胞内组织的，这是本提案的目的。在这里，我们将研究免疫细胞如何在细胞内形成炎性体，它是如何被破坏的，并确定这种破坏过程是否对细胞有任何后果。通过确定炎症小体在细菌感染和炎症刺激下形成的机制，这将有助于我们确定抗炎药物的新靶点，从而有助于开发针对许多重要疾病的新疗法。

Inflammation protects people against infections, but it can be over activated, for example in sepsis or sterile inflammation, where it causes severe disease. Sepsis caused 20% of all global deaths in 2017, but the severe disease caused by COVID-19 has markedly increased this death toll. Sterile inflammation underpins diseases such as arthritis, type II diabetes, cancer, chronic respiratory diseases, atherosclerosis, Alzheimer's and Parkinson's diseases with a growing global burden. In the UK over 20 million people live with arthritis and approximately 850,000 people live with dementia costing £26 billion a year with cases forecast to reach 2 million by 2051. Globally 545 million people live with chronic respiratory disease. Development of new drugs for sepsis and for chronic inflammatory conditions are badly needed because the current ones are either not very efficient and/or have nasty side effects. Receptors present inside the cell (NOD-like receptors (NLRs)) sense pathogens or sterile inflammatory stimuli to form a complex called the inflammasome which ultimately kills the cell. Inflammasome complexes are critical for driving inflammation so to develop better anti-inflammatory therapies it is essential to understand how the inflammasome complex is organized within cells which is the aim of this proposal. Here we will study how immune cells form the inflammasome within cells, how it may be disrupted and determine whether there are any consequences for the cell by this disruptive process. By determining the mechanisms by which inflammasomes form in response to bacterial infection and inflammatory stimuli this will help us identify new targets for anti-inflammatory drugs and hence help develop new therapies for many important diseases.