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: 8079701
• 负责人: Valeria Raquel Mas
• 金额: $ 7.17万
• 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 2012-01-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079701
• 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; Health; 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; Reverse Transcriptase Polymerase Chain Reaction; 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; 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）：肾移植功能丧失伴有肾小管萎缩（TA）和间质纤维化（IF），一组称为慢性同种异体移植肾病（CAN）的发现，导致大多数同种异体移植肾丧失，并且仍然是肾移植（KTx）中的重大临床挑战。 辨别诱发和触发 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导致 CAN 的独特且可识别的因素如何影响移植物中的分子途径，从而逐渐导致慢性同种异体移植物功能障碍。具体假设是，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，以进行早期诊断，并通过发现因果机制来识别可能的治疗方案。 我们的假设基于以下观察结果：1）当在已确定的损伤情况下对移植物进行采样时，CAN 的潜在触发因素实际上可能无法破译；2）许多涉及慢性同种异体移植物损伤和纤维发生的途径可能在损伤过程的早期就受到调节，而这些改变的下游影响在病理学上仍然不明显。 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确定 CAN 疾病进展的早期分子标记的作用。 我们将通过针对以下具体目标进行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-To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期间肾同种异体移植物活检（侵入性监测）中观察到的变化有关。我们将使用基因表达策略来研究同种异体肾移植物、尿液样本和 PBMC 中存在的差异，以识别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 早期诊断和预后中的临床效用。我们将在 PBMC 和尿液样本中使用实时 RT-PCR，在独立的患者组中使用有限的一组标记物来测试这些新生物标记物的预测价值。我们将证明这组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实验以直接测试 CAN 可能的因果机制非常有用。公共卫生相关性：尽管免疫抑制方面取得了进展，但慢性同种异体移植肾病（CAN）导致大多数同种异体移植肾损失，并且仍然是提高长期移植物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。辨别诱发和触发 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。