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，脓毒症导致全球20%的死亡，但COVID-19导致的严重疾病显著增加了这一死亡人数。无菌性炎症是关节炎、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，全球负担日益增加。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。迫切需要开发用于脓毒症和慢性炎症的新药，因为目前的药物要么不是非常有效，要么有严重的副作用。存在于细胞内的受体（NOD样受体（NLR））感知病原体或无菌炎症刺激物，形成一种称为炎性小体的复合物，最终杀死细胞。炎症体复合物对于驱动炎症是至关重要的，因此为了开发更好的抗炎疗法，必须了解炎症体复合物如何在细胞内组织，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小体，它如何被破坏，并确定这种破坏性过程是否对细胞有任何影响。通过确定炎症小体响应细菌感染和炎症刺激而形成的机制，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.