Signalling pathways to Proteinuria

蛋白尿的信号通路

• 批准号: MR/L002418/1
• 负责人: Moin Saleem
• 金额: $ 65.93万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL002418%2F1
• 关键词: Signalling; pathways; Proteinuria

A major factor in morbidity and mortality worldwide is end stage renal disease (ESRD). The UK currently has around 40,000 patients on renal replacement therapy, over 650 per million population, at a cost of over £700 million per year resulting in 2% of the NHS budget being spent on less that 0.1 % of the population. At least 10% of ESRD is caused by steroid resistant nephrotic syndrome (SRNS). This devastating disease is typically associated with oedema, proteinuria, hypertension, microscopic haematuria, and renal insufficiency and usually leads to end stage renal failure despite the use of prolonged and toxic immunosuppression. A difficult and intriguing aspect of SRNS is that in many cases, it will recur following kidney transplantation. The incidence of SRNS, which is particularly common in children, has increased markedly recently with the latest epidemiological study showing a dramatic increase in SRNS as a proportion of primary glomerulopathy from 17 to 59% between 1992 and 2002. Although the cause of SRNS is still unknown, the fact that up to 60% of patients who receive a first kidney transplant to treat their SRNS, experience recurrence of the condition suggests that the cause is not just a result of intrinsic kidney disease. The recurrence of the disease in transplanted patients (often within minutes or hours of the graft being perfused) and the fact that immunosuppressive drug therapy and plasma exchange have proven to be useful in treating the recurrence of SRNS led to the 'circulating toxic factor hypothesis' in the pathogenesis of the disease. The kidney filtration barrier is made up of two cell types: glomerular endothelial cells and podocytes. We have and others have shown that the podocyte is specifically damaged in SRNS and also provided robust evidence that the toxic SRNS factor belongs to a class of proteins known as proteases. Proteases bind to specific receptors (PARs) on the surface of cells leading to changes in cell biology. The purpose of this application is to (1) identify changes in proteases in the plasma of patients with SRNS (2) study the role of PARs in the modulation of podocyte cell health(3) identify the cellular signalling pathways that mediate these effects.Identifying the cellular mechanisms underlying the development of SRNS is essential given its clinical importance and is a critical step in designing and developing targeted therapeutic approaches to deal with this problem.

终末期肾病（ESRD）是全球发病率和死亡率的主要因素。英国目前约有40，000名患者接受肾脏替代治疗，每百万人口超过650人，每年的费用超过7亿英镑，导致NHS预算的2%用于不到0.1%的人口。至少10%的ESRD是由类固醇耐药肾病综合征（SRNS）引起的。这种破坏性疾病通常与水肿、蛋白尿、高血压、显微镜下血尿和肾功能不全相关，并且通常导致终末期肾衰竭，尽管使用长期和毒性免疫抑制剂。SRNS的一个困难和有趣的方面是，在许多情况下，它会在肾移植后复发。SRNS在儿童中特别常见，其发病率最近显著增加，最新的流行病学研究显示，1992年至2002年间，SRNS占原发性肾小球病的比例从17%急剧增加至59%。虽然SRNS的原因仍然未知，但高达60%接受首次肾移植治疗SRNS的患者会复发，这一事实表明原因不仅仅是固有肾脏疾病的结果。移植患者的疾病复发（通常在移植物灌注后数分钟或数小时内）以及免疫抑制药物治疗和血浆置换已被证明可用于治疗SRNS复发的事实导致了疾病发病机制中的“循环毒性因子假说”。肾脏滤过屏障由两种细胞组成：肾小球内皮细胞和足细胞。我们和其他人已经表明，足细胞在SRNS中特异性受损，并且还提供了强有力的证据表明毒性SRNS因子属于一类称为蛋白酶的蛋白质。蛋白酶与细胞表面的特异性受体（PAR）结合，导致细胞生物学的变化。本申请的目的是（1）鉴定SRNS患者血浆中蛋白酶的变化（2）研究PAR在调节足细胞健康中的作用（3）确定介导这些效应的细胞信号通路。鉴于SRNS的临床重要性，确定SRNS发生的细胞机制至关重要，也是设计和开发靶向治疗方法的关键步骤来解决这个问题。

项目成果

Molecular Analysis of Goodpasture's Disease Following Hematopoietic Stem Cell Transplant in a Pediatric Patient, Recalls the Conformeropathy of Wild-Type Anti-GBM Disease.

对儿科患者造血干细胞移植后古德帕斯彻氏病的分子分析，回顾了野生型抗 GBM 疾病的适形病。

• DOI: 10.3389/fimmu.2019.02659
• 发表时间: 2019
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Gray,PaulE;McCarthy,Hugh;Siggs,OwenM;Saleem,MoinA;O'Brien,Tracy;Frith,Katie;Ziegler,JohnB;Kitching,ARichard;Fogo,AgnesB;Hudson,BillyG;Pedchenko,Vadim
• 通讯作者: Pedchenko,Vadim

VEGF regulates local inhibitory complement proteins in the eye and kidney.

• DOI: 10.1172/jci86418
• 发表时间: 2017-01-03
• 期刊: The Journal of clinical investigation
• 作者: Keir LS;Firth R;Aponik L;Feitelberg D;Sakimoto S;Aguilar E;Welsh GI;Richards A;Usui Y;Satchell SC;Kuzmuk V;Coward RJ;Goult J;Bull KR;Sharma R;Bharti K;Westenskow PD;Michael IP;Saleem MA;Friedlander M
• 通讯作者: Friedlander M

BK virus nephropathy without haemorrhagic cystitis following bone marrow transplantation.

骨髓移植后不伴出血性膀胱炎的 BK 病毒肾病。

• DOI: 10.1111/bjh.16234
• 发表时间: 2020
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Ghinai R

Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice.

• DOI: 10.1038/nm.4287
• 发表时间: 2017-04
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Beckerman P;Bi-Karchin J;Park AS;Qiu C;Dummer PD;Soomro I;Boustany-Kari CM;Pullen SS;Miner JH;Hu CA;Rohacs T;Inoue K;Ishibe S;Saleem MA;Palmer MB;Cuervo AM;Kopp JB;Susztak K
• 通讯作者: Susztak K

Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management

• DOI: 10.1016/j.kint.2016.10.013
• 发表时间: 2017-04-01
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Bierzynska, Agnieszka;McCarthy, Hugh J.;Saleem, Moin A.
• 通讯作者: Saleem, Moin A.