Molecular pathways leading to chronic graft dysfunction

导致慢性移植物功能障碍的分子途径

• 批准号: 8419595
• 负责人: Valeria Raquel Mas
• 金额: $ 27.81万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8419595
• 关键词: Molecular; pathways; leading; chronic; graft

DESCRIPTION (provided by applicant): Loss of kidney graft function with tubular atrophy (TA) and interstitial fibrosis (IF), a set of findings termed chronic allograft nephropathy (CAN), causes most kidney allograft losses and remains a significant clinical challenge in kidney transplantation (KTx). Discerning the initial molecular events that predispose and trigger CAN represents the best design for improving long-term graft survival rates. Our long-term goal is to determine how the distinct and identifiable factors causing CAN affect the molecular pathways in the graft that progressively lead to chronic allograft dysfunction. The specific hypothesis is that the elucidation of correlations between gene expression profiles and progression to CAN in kidney transplant patients will allow the identification and use of biomarkers in non-invasive assays for early diagnosis and the recognition of possible therapeutic options through the discovery of causal mechanisms. We base the hypothesis on the observations that 1) underlying triggers for CAN may in fact be impossible to decipher, when the graft is sampled with established injury and, 2) many of the pathways involved in chronic allograft injury and fibrogenesis might be regulated very early in the course of the injury when the downstream effects of these alterations are still not evident by pathology. Therefore, these observations justify a role of early graft sampling by microarray technology to identify early molecular markers for CAN disease progression. We will test our hypothesis by carrying out experiments directed at the following specific aims: 1- To elucidate the genes associated with the progression to chronic graft dysfunction in kidney transplant allografts for both the development of useful biomarkers to predict CAN and for the elucidation of causal mechanisms of CAN. We will prospectively study gene expression profiling in graft biopsies at pre-implantation, post reperfusion and during the first 9 months post-KTx. 2-To demonstrates that differential gene expression in peripheral blood mononuclear cells (PBMC) or/and urine cells (non-invasive monitoring) are related to the changes observed in the renal allograft biopsies (invasive monitoring) during progression to CAN. We will study differences that exist in the kidney allograft, urine samples and in PBMC using gene expression strategies for identifying new non-invasive biomarkers. 3-To prospectively establish the clinical utility of using the selected biomarkers in the early diagnosis and prognosis of CAN. We will use real time-RT-PCR in PBMC and urine samples employing a limited panel of markers in an independent group of patients to test the predictive value of these new biomarkers. We will demonstrate that this panel of biomarkers can predict early changes leading to CAN, which can be useful in managing the patient and in designing more sophisticated hypothesis driven experiments to directly test possible causal mechanisms of CAN. PUBLIC HEALTH RELEVANCE: Despite of progresses in immunosuppression, chronic allograft nephropathy (CAN) causes most kidney allograft losses and remains the main clinical challenge for improving long-term graft survival rate. The pathophysiology of CAN remains poorly understood and requires further prospective study using human allograft tissue. Discerning the initial molecular events that predispose and trigger CAN represents the best design for improving long-term graft survival rates.

描述（由申请人提供）：肾移植功能丧失肾脏萎缩（TA）和间质纤维化（如果）（如果），一组被称为慢性同种异体同种异体肾病（CAN）的发现会导致大多数肾脏同种异体移植物损失，并且仍然是肾脏移植（KTX）中的临床挑战。 辨别易感和触发的初始分子事件可以代表提高长期移植生存率的最佳设计。 我们的长期目标是确定引起的不同和可识别的因子如何影响移植物中的分子途径，从而逐渐导致同种异体移植功能障碍。具体的假设是，在肾脏移植患者中阐明基因表达谱和向CAN的相关性阐明将允许在非侵入性测定中鉴定和使用生物标志物，以早期诊断，并通过发现因果机制发现可能的治疗选择。 我们基于观察结果的基础，即1）当移植物被既定损伤取样时，可能无法破译可能的潜在触发因素，而2）当这些改变的下降剂量不受通路的影响时，可能会在很早的损伤过程中就很早就受到损害的早期来调节慢性同种异体移植损伤和纤维发生的许多途径。 因此，这些观察结果证明了微阵列技术早期移植物对鉴定疾病进展的早期分子标记的作用。 我们将通过执行针对以下特定目的的实验来检验我们的假设：1-阐明与肾移植同种异体移植物中慢性移植功能障碍相关的基因，以预测有用的生物标志物可以预测CAN，并阐明CAN的因果机制。我们将前瞻性研究在植入前，再灌注后以及KTX后的前9个月中，在移植活检中进行基因表达分析。 2表明，外周血单核细胞（PBMC）或/和尿液细胞（非侵入性监测）中的差异基因表达与在进展到CAN过程中肾脏同种异体移植活检（侵入性监测）中观察到的变化有关。我们将使用鉴定新的非侵入性生物标志物的基因表达策略研究肾脏同种异体移植，尿液样本和PBMC中存在的差异。 3前瞻性地建立在罐头的早期诊断和预后中使用所选生物标志物的临床实用性。我们将在PBMC和尿液样品中使用实时RT-PCR，在独立的患者组中使用有限的标记面板来测试这些新生物标志物的预测价值。我们将证明，该小组的生物标志物可以预测导致CAN的早期变化，这对于管理患者和设计更复杂的假设驱动的实验可以直接测试CAN可能的因果机制。公共卫生相关性：尽管在免疫抑制方面取得了进展，但同种异体同种异体肾病（CAN）仍会导致大多数肾脏同种异体移植损失，并且仍然是提高长期移植物存活率的主要临床挑战。罐头的病理生理学仍然知之甚少，需要使用人类同种异体移植组织进行进一步的前瞻性研究。辨别易感和触发的初始分子事件可以代表提高长期移植生存率的最佳设计。