Endothelial microparticles in patients with kidney transplants
肾移植患者的内皮微粒
基本信息
- 批准号:8323889
- 负责人:
- 金额:$ 22.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-23 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAllograftingAnimalsAntibodiesAntigensApoptoticBiological MarkersBiopsyBlood VesselsBlood capillariesCell Surface ProteinsCell physiologyCellsCirrhosisCreatinineDataDiagnosisEnd stage renal failureEndothelial CellsEndotheliumFailureFunctional disorderGoalsGoldGraft SurvivalHepatitis CHistologicImmunosuppressionIn VitroKidneyKidney TransplantationMajor Histocompatibility ComplexMeasuresMediatingMembraneOperative Surgical ProceduresOrgan TransplantationPathogenesisPathologyPatientsPatternPilot ProjectsPlayProceduresProductionProteinsQuality of lifeRoleSerumSolidStaining methodStainsStressSurrogate MarkersTechniquesTestingTransplant RecipientsVesicleallograft rejectionbasecapillarycell typeclinically significantcomplement C4dimprovedkidney allograftliver transplantationnovelnovel markerresearch clinical testing
项目摘要
DESCRIPTION (provided by applicant): This proposal seeks to establish levels of circulating endothelial microparticles (EMP) as a novel biomarker of allograft rejection in the setting of kidney transplantation. Endothelial cells (EC) play an important role in the pathogenesis of allograft dysfunction and rejection. With improved immunosuppression and surgical technique, graft survival has significantly increased. Nevertheless, allograft rejection remains one of the main causes for allograft failure. The endothelium is one of the main targets in allograft rejection, especially antibody-mediated rejection (AMR). Typically, renal allograft function is evaluated by serum creatinine (SC) levels. Unfortunately, SC level elevation is a non-specific marker of renal allograft dysfunction, and it may occur in many different conditions. The "gold standard" test for the assessment of allograft rejection is renal allograft biopsy, which is an invasive, expensive and relatively risky procedure. The patterns of acute cellular rejection (ACR) are well-documented and broadly recognized. However, diagnosis of AMR is one of the most challenging in renal pathology. Peritubular capillary (PTC) C4d staining is one of the markers of AMR. Still, some kidney biopsies show C4d staining without histologic findings of AMR or ACR. Recently, evidence that some forms of AMR may be negative for PTC C4d staining has been described. Based on these data, the need for a reliable and clinically significant marker of allograft rejection is emerging. Microparticles are small membrane vesicles shed by different cell types, which contain cell surface proteins and cytoplasmic components of the original cell. The microparticle production is a part of normal cell function, but it increases by apoptotic cells and cells under stress. Others and we had previously demonstrated that levels of circulating EMP may be used as a surrogate marker of EC dysfunction. Recent studies have indicated changes in circulating EMP levels in patients with solid organ transplants, including kidneys. We demonstrated that circulating EMP levels, initially elevated in patients with Hepatitis C cirrhosis, were decreased to the levels seen in healthy people two weeks after liver transplantation. This data suggests that the levels of circulating EMP may be useful as a biomarker of EC function in patients with solid organ transplants. Based on these findings, we hypothesize that 1) an elevation in circulating EMP levels may be a novel marker of renal allograft rejection; 2) EMP produced by the renal allograft endothelium are different by their protein composition from EMP produced by the recipient endothelium; therefore, the former may be used as the biomarker of EC function of the renal allograft. Our hypotheses will be tested under two specific aims: 1) evaluate if the levels of circulating endothelial microparticles can be used as a marker of allograft rejection in patients with kidney transplants; 2) undertake a pilot study to investigate if the pool of circulating EMP may be further separated in order to distinguish between the microparticles produced by the recipient and allograft endothelium. Conclusions: This R21 is the essential step to advance the study of EMP as the novel marker of rejection in renal transplant patients.
描述(由申请人提供):该提案旨在确定循环内皮微粒(EMP)的水平,作为肾移植中同种异体移植排斥的新生物标志物。内皮细胞(EC)在同种异体移植物功能障碍和排斥反应的发病机制中发挥着重要作用。随着免疫抑制和手术技术的改进,移植物的存活率显着增加。尽管如此,同种异体移植排斥仍然是同种异体移植失败的主要原因之一。内皮是同种异体移植排斥反应的主要靶点之一,尤其是抗体介导的排斥反应(AMR)。通常,同种异体移植肾功能是通过血清肌酐(SC)水平来评估的。不幸的是,SC 水平升高是同种异体移植肾功能障碍的非特异性标志物,并且可能发生在许多不同的情况下。评估同种异体移植排斥的“金标准”测试是肾同种异体移植物活检,这是一种侵入性、昂贵且相对危险的程序。急性细胞排斥(ACR)的模式已有详细记录并得到广泛认可。然而,AMR 的诊断是肾脏病理学中最具挑战性的诊断之一。管周毛细血管 (PTC) C4d 染色是 AMR 的标志物之一。尽管如此,一些肾活检显示 C4d 染色,但没有 AMR 或 ACR 的组织学发现。最近,有证据表明某些形式的 AMR 可能对 PTC C4d 染色呈阴性。基于这些数据,对同种异体移植排斥的可靠且具有临床意义的标记物的需求正在出现。 微粒是不同细胞类型脱落的小膜囊泡,含有细胞表面蛋白和原始细胞的细胞质成分。微粒的产生是正常细胞功能的一部分,但它会因凋亡细胞和应激下的细胞而增加。我们和其他人之前已经证明循环 EMP 水平可以用作 EC 功能障碍的替代标志。最近的研究表明,实体器官移植患者(包括肾脏)的循环 EMP 水平发生了变化。我们证明,最初在丙型肝炎肝硬化患者中升高的循环 EMP 水平在肝移植后两周下降到健康人的水平。该数据表明,循环 EMP 水平可作为实体器官移植患者 EC 功能的生物标志物。基于这些发现,我们假设 1) 循环 EMP 水平升高可能是肾同种异体移植排斥的新标志物; 2)同种异体移植肾内皮产生的EMP与受体内皮产生的EMP在蛋白质组成上有所不同;因此,前者可作为同种异体肾移植肾EC功能的生物标志物。我们的假设将在两个具体目标下进行测试:1)评估循环内皮微粒的水平是否可以用作肾移植患者同种异体移植排斥的标志物; 2) 进行初步研究,调查是否可以进一步分离循环 EMP 池,以区分受体和同种异体移植物内皮产生的微粒。 结论:R21 是推进 EMP 作为肾移植患者排斥反应新标志物研究的重要一步。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Early posttransplant changes in circulating endothelial microparticles in patients with kidney transplantation.
- DOI:10.1016/j.trim.2014.06.006
- 发表时间:2014-08
- 期刊:
- 影响因子:1.5
- 作者:Qamri Z;Pelletier R;Foster J;Kumar S;Momani H;Ware K;Von Visger J;Satoskar A;Nadasdy T;Brodsky SV
- 通讯作者:Brodsky SV
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SERGEY BRODSKY其他文献
SERGEY BRODSKY的其他文献
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{{ truncateString('SERGEY BRODSKY', 18)}}的其他基金
Endothelial microparticles in patients with kidney transplants
肾移植患者的内皮微粒
- 批准号:
8188907 - 财政年份:2011
- 资助金额:
$ 22.88万 - 项目类别:
ENDOTHELIAL DYSFUNCTION: FORMATION OF MICROPARTICLES
内皮功能障碍:微粒的形成
- 批准号:
6942957 - 财政年份:2004
- 资助金额:
$ 22.88万 - 项目类别:
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