Biomarker Discovery in Chronic Graft-vs-Host Disease

慢性移植物抗宿主病的生物标志物发现

• 批准号: 7881588
• 负责人: John Andrew Hansen
• 金额: $ 44万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-17 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881588
• 关键词: Address; Allogenic; Alternative Splicing; Ancillary Study; Antibodies; Biological Assay; Biological Markers; Candidate Disease Gene; Caring; Case-Control Studies; Chronic; Clinical; Clinical Trials; Cohort Studies; Consent; Consent Forms; Dana-Farber Cancer Institute; Development; Diagnosis; Diagnostic; Disease; Effectiveness; Enrollment; Exons; Family; Fred Hutchinson Cancer Research Center; Funding; Gene Expression; Goals; Grant; Health care facility; Hematopoietic Stem Cell Transplantation; Human; Immunosuppression; Letters; Mass Spectrum Analysis; Methods; Minnesota; Modification; Monitor; Mononuclear Leukocytes; Morbidity - disease rate; Outcome Assessment; Participant; Patients; Peripheral Blood Mononuclear Cell; Phase; Physicians; Plasma; Proteins; Proteomics; Protocols documentation; Research Ethics Committees; Research Personnel; Resolution; Sampling; Sampling Studies; Sensitivity and Specificity; Severities; Site; Staging; Study Subject; Survivors; Symptoms; Therapeutic Intervention; United States National Institutes of Health; Universities; Validation; Variant; abstracting; base; cancer care; candidate validation; chronic graft versus host disease; disorder control; genome wide association study; genome-wide analysis; graft vs host disease; improved; innovative technologies; insight; mortality; novel; peripheral blood; response; sample collection; tool; treatment response; treatment strategy; validation studies; willingness

DESCRIPTION (provided by applicant): Chronic graft-versus-host disease (cGVHD) occurs in 50-70% of patients following allogeneic hematopoietic stem cell transplantation (HSCT) and is a major cause of morbidity and mortality. The clinical manifestations of cGVHD are diverse and variable, and the diagnosis, staging and assessment of response to therapeutic interventions have been difficult to standardize. There are no signs or symptoms or diagnostic tools that predict the development or severity of cGVHD, or the need for immune suppression therapy. The goal of this proposal is to address these unmet needs by identifying novel biomarkers that are associated with the onset and severity of cGVHD. The initial phase of study will consist of a parallel discovery strategy that employs a genome-wide analysis of transcriptional changes in peripheral blood mononuclear cells (PBMC) together with a high-resolution, high-sensitivity quantitative proteomic analysis to identify informative proteins in plasma that correlate with disease activity. These transcriptional changes and proteins will be prioritized to develop a list of candidates for second phase validation studies to confirm and further define a panel of markers that together provide high sensitivity and specificity for the diagnosis of cGVHD and the prediction of severity and/or treatment response. Aim 1 of this study is to identify novel biomarkers in peripheral blood for the diagnosis of cGVHD using dual approaches: 1a) analysis of global gene expression and alternate splicing in mononuclear leucocytes; and 1b) quantitative in-depth profiling of circulating proteins in plasma. The transcriptional analysis will be performed on PBMC using the Affymetrix Human Exon 1.0 ST array, and the proteomic analysis will be performed on plasma by mass spectrometry. Aim 2 will focus on the validation of candidate biomarkers identified in an independent, multicenter cohort study of cGVHD. Candidate genes and alternate splice variants will be validated by PCR-based assays, and candidate proteins will be validated by antibody-based assays. This application is submitted in response to RFA-HL-08-001, titled "Ancillary Studies in Clinical trials (R01)." We are proposing a biomarker discovery and validation project that is focused on cGVHD occurring after allo HSCT. The subjects for this study, cases and controls, will be enrolled in a separate NIH funded multi-center study titled "Improving outcomes assessment in chronic GVHD" (R01-CA118953; Dr. Stephanie Lee, PI). Participating Centers include the Dana-Farber Cancer Institute (DFCI), the Seattle Cancer Care Alliance (SCCA)/Fred Hutchinson Cancer Research Center (FHCRC), Stanford University and the University of Minnesota. Total enrollment across the sites will reach 336 incident and 336 prevalent cGVHD cases. Patients will be followed for three years, and systematically evaluated for cGVHD status and response to cGVHD therapy. Chronic graft-versus-host disease (cGVHD) occurs in 50-70% of patients following allogeneic hematopoietic stem cell transplantation (HSCT) and is a major cause of morbidity and mortality. As the utilization of HSCT and number of HSCT survivors increases, the issue of cGVHD becomes a greater concern not only to patients and their families but also to the specialized physicians and health care facilities responsible for their care. The studies proposed here are aimed at improving methods for the diagnosis of cGVHD, monitoring disease activity and the effectiveness of cGVHD therapy. These studies may also yield insights into the underlying disorders responsible for cGVHD and thereby suggest new treatment strategies. (End of Abstract)

描述（由申请人提供）： 在同种异体造血干细胞移植（HSCT）之后，在50-70％的患者中发生了慢性移植抗宿主病（CGVHD），是发病率和死亡率的主要原因。 CGVHD的临床表现是多种多样和可变的，对治疗干预措施的诊断，分期和评估很难标准化。没有预测CGVHD发展或严重性的迹象，症状或诊断工具，或者需要进行免疫抑制疗法。该提案的目的是通过识别与CGVHD的发作和严重性相关的新型生物标志物来满足这些未满足的需求。研究的初始阶段将包括一个平行的发现策略，该策略对周围血液单核细胞（PBMC）的转录变化进行了全基因组分析，以及高分辨率的高敏量定量蛋白质组学分析，以鉴定与疾病活性相关的等离子体中信息蛋白的信息。这些转录变化和蛋白质将优先考虑第二阶段验证研究的候选列表，以确认并进一步定义了一系列标记，这些标记共同为诊断CGVHD提供了高灵敏度和特异性，并预测了严重性和/或治疗反应的预测。这项研究的目的1是使用双重方法鉴定外周血中的新生物标志物来诊断CGVHD：1A）分析全球基因表达和单核白细胞中的替代剪接；和1B）血浆中循环蛋白的深入分析。转录分析将使用Affymetrix人外显子1.0 ST阵列在PBMC上进行，蛋白质组学分析将通过质谱法对等离子体进行。 AIM 2将重点介绍在CGVHD的独立多中心队列研究中鉴定的候选生物标志物的验证。候选基因和替代剪接变体将通过基于PCR的分析来验证，候选蛋白将通过基于抗体的测定验证。该申请是针对RFA-HL-08-001的响应，标题为“临床试验中的辅助研究（R01）”。我们提出了一个生物标志物发现和验证项目，该项目集中在Allo HSCT后发生的CGVHD上。这项研究的受试者，病例和对照组将参加单独的NIH资助的多中心研究，标题为“改善慢性GVHD的结果评估”（R01-CA118953； Stephanie Lee，PI）。参与中心包括Dana-Farber癌症研究所（DFCI），西雅图癌症护理联盟（SCCA）/弗雷德·哈钦森癌症研究中心（FHCRC），斯坦福大学和明尼苏达大学。整个站点的总入学人数将达到336起事件和336例普遍的CGVHD病例。患者将进行三年，并系统地评估CGVHD状态和对CGVHD疗法的反应。在同种异体造血干细胞移植（HSCT）之后，在50-70％的患者中发生了慢性移植抗宿主病（CGVHD），是发病率和死亡率的主要原因。随着HSCT的利用和HSCT幸存者数量的增加，CGVHD的问题不仅对患者及其家人，而且对负责其护理的专业医师和医疗保健设施也更加关注。此处提出的研究旨在改善诊断CGVHD，监测疾病活动和CGVHD治疗有效性的方法。这些研究还可能对负责CGVHD的潜在疾病产生见解，从而提出新的治疗策略。 （抽象的结尾）