The Role of Membrane Attack Complex in Atypical Haemolytic Uraemic Syndrome

膜攻击复合物在非典型溶血性尿毒症综合征中的作用

• 批准号: MR/R001359/1
• 负责人: Kate Smith-Jackson
• 金额: $ 37.25万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR001359%2F1
• 关键词: Role; Membrane; Attack; Complex; Atypical

Atypical haemolytic uraemic syndrome (aHUS) is a kidney disorder which without treatment rapidly progresses to kidney failure. Until recently, renal transplantation has been contraindicated due to the high recurrence rate. Over the last 20 years research into aHUS has found that it results from over activation of the complement system due to loss of its integral regulation. The complement system is an ancient defence mechanism which protects the body from foreign cells and removes our own damaged ones. In certain conditions, people lack the ability to regulate the complement system, this in turn allows the complement system to attack healthy tissue which subsequently causes disease. In aHUS people have genetic mutations for key complement proteins, this results in a defective protein being produced, which is unable to function normally, this in turn then causes them to develop disease. After research had shown the role of the complement system in aHUS, it led to the use of the drug 'Eculizumab' which has transformed patients' lives. This drugs works by 'switching' off the final pathway of the complement system, preventing the direct attack on healthy cells and preventing the creation of an inflammatory environment. However, the drug is very costly and as it silences one of the body's defences against foreign cells it can make people vulnerable to serious, life threatening infections. In light of the above we have developed a comparative model of aHUS which will allow us to investigate the 'terminal pathway' of the complement system. My experiments will determine which protein of the terminal pathway is responsible for the development of disease. Once we have defined the proteins role in disease we will be able to inhibit its function by using a targeted drug therapy. This will confirm our understanding of the basic mechanisms of the disease whilst simultaneously testing a targeted therapy in a pre-clinical model. This will enable me to develop and deliver a targeted treatment for patients; reducing their risks of increased infection and improve health economics for all. My experiments will provide detailed data regarding the efficacy of the current front line anti-complement therapy in this model, and will heavily inform and dictate whether new complement therapeutics in pre-clinical evaluation can provide better protection for patients in the future. The terminal pathway of the complement system is critical to the development of many more diseases; stemming from sepsis to spinal cord injury. Understanding the roles of the terminal pathway proteins in a model of complement dysregulation (my comparative model of aHUS) will significantly contribute to an improved overall understanding; producing translatable benefits to a wide variety of disease and begin to provide an understanding of anti-complement therapies in these conditions.

非典型溶血性尿毒综合征（aHUS）是一种肾脏疾病，未经治疗会迅速发展为肾衰竭。直到最近，由于高复发率，肾移植一直是禁忌。在过去的20年里，对aHUS的研究发现，它是由于补体系统失去其整体调节而过度激活的结果。补体系统是一种古老的防御机制，它保护身体免受外来细胞的侵害，并清除我们自己受损的细胞。在某些情况下，人们缺乏调节补体系统的能力，这反过来又使补体系统攻击健康组织，从而导致疾病。在aHUS患者中，关键的补体蛋白发生了基因突变，这导致产生了一种有缺陷的蛋白质，无法正常发挥作用，这反过来又导致他们患上疾病。在研究显示了补体系统在aHUS中的作用之后，它导致了“Eculizumab”药物的使用，这改变了患者的生活。这种药物通过“关闭”补体系统的最终途径，防止对健康细胞的直接攻击，防止炎症环境的产生。然而，这种药物非常昂贵，而且由于它会使人体对外来细胞的一种防御功能失效，它可能使人们容易受到严重的、威胁生命的感染。鉴于上述情况，我们开发了一个aHUS的比较模型，这将使我们能够研究补体系统的“终端途径”。我的实验将确定最终途径中的哪一种蛋白质是导致疾病发展的原因。一旦我们确定了蛋白质在疾病中的作用，我们将能够通过使用靶向药物治疗来抑制其功能。这将证实我们对疾病基本机制的理解，同时在临床前模型中测试靶向治疗。这将使我能够为患者开发和提供有针对性的治疗；减少他们感染增加的风险，改善所有人的卫生经济状况。我的实验将提供关于该模型中当前一线抗补体治疗疗效的详细数据，并将在很大程度上告知和决定临床前评估中的新补体治疗是否能在未来为患者提供更好的保护。补体系统的终末通路对许多疾病的发展至关重要；由败血症引起的脊髓损伤。了解末端通路蛋白在补体失调模型中的作用（我的aHUS比较模型）将显著有助于提高整体理解；对多种疾病产生可转化的益处，并开始提供对这些疾病的抗补体疗法的理解。

项目成果

Atypical haemolytic uraemic syndrome in the era of terminal complement inhibition- An observational cohort study

终末补体抑制时代的非典型溶血性尿毒症综合征——一项观察性队列研究

• DOI: 10.57711/3q67-3p90
• 发表时间: 2023
• 作者: Brocklebank V, Walsh PR, Smith-Jackson K, Hallam TM, Marchbank KJ, Wilson V, Bigirumurame T, Dutt T, Montgomery EK, Malina M, Wong EKS, Johnson S, Sheerin NS, Kavanagh D

The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.

• DOI: 10.1093/hmg/ddab086
• 发表时间: 2021-06-17
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: McMahon O;Hallam TM;Patel S;Harris CL;Menny A;Zelek WM;Widjajahakim R;Java A;Cox TE;Tzoumas N;Steel DHW;Shuttleworth VG;Smith-Jackson K;Brocklebank V;Griffiths H;Cree AJ;Atkinson JP;Lotery AJ;Bubeck D;Morgan BP;Marchbank KJ;Seddon JM;Kavanagh D
• 通讯作者: Kavanagh D

Targeting properdin in the treatment of atypical haemolytic uraemic syndrome: better than eculizumab?

• DOI: 10.21037/atm.2018.10.35
• 发表时间: 2018-10
• 期刊: Annals of translational medicine
• 作者: K. Smith-Jackson;K. Marchbank

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice.

• DOI: 10.3389/fimmu.2021.752916
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Kamala O;Malik TH;Hallam TM;Cox TE;Yang Y;Vyas F;Luli S;Connelly C;Gibson B;Smith-Jackson K;Denton H;Pappworth IY;Huang L;Kavanagh D;Pickering MC;Marchbank KJ
• 通讯作者: Marchbank KJ

Functional Characterization of Rare Genetic Variants in the N-Terminus of Complement Factor H in aHUS, C3G, and AMD.

• DOI: 10.3389/fimmu.2020.602284
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Wong EKS;Hallam TM;Brocklebank V;Walsh PR;Smith-Jackson K;Shuttleworth VG;Cox TE;Anderson HE;Barlow PN;Marchbank KJ;Harris CL;Kavanagh D
• 通讯作者: Kavanagh D