Inflammasome complex organisation in infectious and inflammatory diseases

感染性和炎症性疾病中的炎症小体复合体组织

• 批准号: MR/X000826/1
• 负责人: Clare Bryant
• 金额: $ 122.72万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX000826%2F1
• 关键词: Inflammasome; complex; organisation; infectious; inflammatory

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.

炎症可以保护人们免受感染的影响，但可能会过度激活，例如在败血症或无菌感染中引起严重疾病。败血症在2017年造成了全球所有死亡人数的20％，但由Covid-19引起的严重疾病显着增加了这一死亡人数。无菌感染是关节炎，II型糖尿病，癌症，慢性呼吸道疾病，动脉粥样硬化，阿尔茨海默氏病和帕金森氏病等疾病的基础。在英国，超过2000万人患有关节炎，大约有85万人患有痴呆症，每年耗资260亿英镑，预计到2051年，案例预计将达到200万。全球5.45亿人患有慢性呼吸道疾病。急需开发用于败血症和慢性炎症状况的新药，因为目前的药物要么不是很有效，而且具有讨厌的副作用。细胞内部存在的受体（点状受体（NLR））有感觉病原体或无菌炎症刺激形成一种称为炎性体的复合物，最终杀死了细胞。炎症体复合物对于驱动感染至关重要，因此要开发出更好的抗炎疗法，必须了解如何在细胞内组织炎性体复合物，这是该提案的目的。在这里，我们将研究免疫细胞在细胞内如何形成炎症体，如何被破坏并确定这种破坏性过程是否对细胞产生任何后果。通过确定炎症响应细菌感染和炎症刺激的机制，这将有助于我们确定抗炎药的新靶标，从而有助于为许多重要疾病开发新的疗法。

项目成果

Inflammasomes as regulators of mechano-immunity.

炎症小体作为机械免疫的调节剂。

• DOI: 10.17863/cam.104519
• 发表时间: 2023
• 作者: Bezbradica J

Inflammasomes as regulators of mechano-immunity

• DOI: 10.1038/s44319-023-00008-2
• 发表时间: 2024-01-12
• 期刊: EMBO REPORTS
• 影响因子: 7.7
• 作者: Bezbradica，Jelena S.;Bryant，Clare E.
• 通讯作者: Bryant，Clare E.

The Achromobacter type 3 secretion system drives pyroptosis and immunopathology via independent activation of NLRC4 and NLRP3 inflammasomes.

• DOI: 10.1016/j.celrep.2023.113012
• 发表时间: 2023-08-29
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Turton K;Parks HJ;Zarodkiewicz P;Hamad MA;Dwane R;Parau G;Ingram RJ;Coll RC;Bryant CE;Valvano MA
• 通讯作者: Valvano MA