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

基本信息

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
项目类别：
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

项目摘要

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）： 50-70% 的异基因造血干细胞移植 (HSCT) 患者会发生慢性移植物抗宿主病 (cGVHD)，是发病和死亡的主要原因。 cGVHD 的临床表现多种多样且多变，诊断、分期和治疗干预反应评估很难标准化。没有迹象或症状或诊断工具可以预测 cGVHD 的发展或严重程度，或是否需要免疫抑制治疗。该提案的目标是通过识别与 cGVHD 的发病和严重程度相关的新型生物标志物来解决这些未满足的需求。研究的初始阶段将包括并行发现策略，该策略采用外周血单核细胞（PBMC）转录变化的全基因组分析以及高分辨率、高灵敏度定量蛋白质组分析来识别血浆中的信息蛋白，与疾病活动度相关。这些转录变化和蛋白质将优先开发第二阶段验证研究的候选者名单，以确认和进一步定义一组标记物，这些标记物共同为 cGVHD 的诊断以及严重程度和/或治疗反应的预测提供高灵敏度和特异性。本研究的目的 1 是使用双重方法鉴定外周血中用于诊断 cGVHD 的新型生物标志物：1a) 分析单核白细胞中的整体基因表达和可变剪接； 1b) 血浆中循环蛋白的定量深入分析。将使用 Affymetrix Human Exon 1.0 ST 阵列对 PBMC 进行转录分析，并通过质谱法对血浆进行蛋白质组分析。目标 2 将重点验证在一项独立、多中心的 cGVHD 队列研究中确定的候选生物标志物。候选基因和可变剪接变体将通过基于 PCR 的测定进行验证，候选蛋白质将通过基于抗体的测定进行验证。本申请是响应 RFA-HL-08-001 提交的，标题为“临床试验中的辅助研究 (R01)”。我们正在提议一个生物标志物发现和验证项目，重点关注 allo HSCT 后发生的 cGVHD。本研究的受试者（病例和对照）将参加一项单独的 NIH 资助的多中心研究，题为“改善慢性 GVHD 的结果评估”（R01-CA118953；Stephanie Lee 博士，PI）。参与中心包括达纳法伯癌症研究所 (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。各中心的登记总数将达到 336 例 cGVHD 病例和 336 例流行的 cGVHD 病例。患者将被随访三年，并系统评估 cGVHD 状态和对 cGVHD 治疗的反应。 50-70% 的异基因造血干细胞移植 (HSCT) 患者会发生慢性移植物抗宿主病 (cGVHD)，是发病和死亡的主要原因。随着 HSCT 的使用和 HSCT 幸存者数量的增加，cGVHD 问题不仅成为患者及其家属的更大关注，也成为负责其护理的专科医生和医疗机构的更大关注。这里提出的研究旨在改进 cGVHD 的诊断方法、监测疾病活动性和 cGVHD 治疗的有效性。这些研究还可能深入了解导致 cGVHD 的潜在疾病，从而提出新的治疗策略。（摘要完）