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: 7822882
• 负责人: Valeria Raquel Mas
• 金额: $ 39.03万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 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/7822882
• 关键词: Address; Affect; Allografting; Atrophic; Biological Assay; Biological Markers; Biology; Biopsy; Cells; Chronic; Chronic rejection of renal transplant; Clinical; Correlation Studies; Development; Disease; Disease Progression; Early Diagnosis; Early treatment; Event; Fibrosis; Functional disorder; Future; Gene Expression; Gene Expression Profiling; Genes; Genomics; Goals; Graft Survival; Healed; Human; Immunosuppression; Injury; Kidney; Kidney Transplantation; Lead; Microarray Analysis; Molecular; Molecular Profiling; Monitor; Nephrons; Pathology; Pathway interactions; Patient Monitoring; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Predictive Value of Tests; Probability; Process; Prospective Studies; Reperfusion Therapy; Risk; Role; Sampling; Series; Signal Transduction; Staging; Survival Rate; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue-Specific Gene Expression; Tissues; Transplant Recipients; Transplantation; Tubular formation; Urine; base; design; fibrogenesis; graft function; healing; improved; interstitial; isoimmunity; kidney allograft; minimally invasive; molecular marker; non-invasive monitor; novel marker; outcome forecast; preimplantation; prospective; public health relevance; renal scarring; research study; response; stressor

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）：移植肾功能丧失伴肾小管萎缩（TA）和间质纤维化（IF），一组被称为慢性移植物肾病的结果 (CAN)导致大多数肾移植物丢失，并且仍然是肾移植中的重大临床挑战 （KTx）。 识别易感和触发CAN的初始分子事件代表了提高长期移植物存活率的最佳设计。 我们的长期目标是确定引起CAN的不同和可识别的因素如何影响移植物中逐渐导致慢性同种异体移植物功能障碍的分子通路。具体的假设是，阐明肾移植患者基因表达谱与CAN进展之间的相关性，将允许在非侵入性检测中识别和使用生物标志物进行早期诊断，并通过发现因果机制识别可能的治疗方案。 我们的假设基于以下观察结果：1）当移植物在确定损伤的情况下取样时，CAN的潜在触发因素实际上可能无法破译，（二）许多参与慢性同种异体移植物损伤和纤维形成的途径可能在损伤过程的非常早期受到调节，此时这些改变的下游效应仍然不明显，病理 因此，这些观察结果证明了通过微阵列技术进行早期移植物取样以鉴定CAN疾病进展的早期分子标记物的作用。 我们将通过针对以下具体目标进行实验来测试我们的假设：1-阐明与肾移植同种异体移植物中慢性移植物功能障碍进展相关的基因，以开发预测CAN的有用生物标志物并阐明CAN的因果机制。我们将前瞻性地研究植入前、再灌注后和KTx后前9个月移植物活检中的基因表达谱。 2-证明外周血单核细胞（PBMC）或/和尿细胞（非侵入性监测）中的差异基因表达与进展为CAN期间肾移植物活检（侵入性监测）中观察到的变化相关。我们将使用基因表达策略研究肾移植物、尿液样本和PBMC中存在的差异，以鉴定新的非侵入性生物标志物。 3-前瞻性地建立使用所选生物标志物在CAN的早期诊断和预后中的临床效用。我们将在一组独立的患者中使用PBMC和尿液样本中的真实的时间RT-PCR，采用有限的标志物组来测试这些新生物标志物的预测价值。我们将证明，这一组生物标志物可以预测导致CAN的早期变化，这在管理患者和设计更多的治疗方案方面是有用的。 复杂的假设驱动实验，直接测试CAN的可能因果机制。公共卫生相关性：尽管免疫抑制治疗取得了进展，但慢性移植肾肾病（CAN）仍是导致移植肾丢失的主要原因，也是提高移植肾长期存活率的主要临床挑战。CAN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。识别易感和触发CAN的初始分子事件代表了提高长期移植物存活率的最佳设计。