Longitudinal SIT Trial Plasma Proteomic Biomarker Discovery and Validation in SCI

SCI 中的纵向 SIT 试验血浆蛋白质组生物标志物的发现和验证

• 批准号: 7555939
• 负责人: James F Casella
• 金额: $ 40.21万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555939
• 关键词: Age; Aging; Antibodies; Applications Grants; Area; Arts; Atherosclerosis; Biological Assay; Biological Markers; Brain; Brain Injuries; Brain Ischemia; Cardiovascular system; Cerebral Infarction; Cerebrum; Child; Chronic; Cognitive; Databases; Dementia; Development; Diabetes Mellitus; Diagnostic; Disease; Early treatment; Enrollment; Etiology; Evaluation; Fractionation; Genes; Goals; High Pressure Liquid Chromatography; Hypertension; Individual; Infarction; Infection; Institutes; Lesion; Life; Liquid Chromatography; Magnetic Resonance Imaging; Mass Spectrum Analysis; Migraine; Minority; Modeling; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Outcome; Participant; Pathologic; Patients; Phase; Phenotype; Pilot Projects; Plasma; Plasma Proteins; Population; Proteins; Proteome; Proteomics; Public Health; Randomized; Resources; Risk; Sampling; Sampling Studies; Sickle Cell Anemia; Stroke; Structure; Symptoms; Systemic disease; Techniques; Technology; Therapeutic; Time; Transfusion; Treatment Efficacy; Upper arm; Validation; Western Blotting; abstracting; central nervous system injury; cognitive function; cohort; cost; design; insight; interest; patient population; prognostic; protein expression; protein profiling; response; standard care; success; tv watching

DESCRIPTION (provided by applicant): Silent cerebral infarctions (SCI) occur in 22% of children with sickle cell disease (SCD) and are associated with decreased cognitive function. By definition, these children have MRI and pathologic evidence consistent with brain ischemia or infarction, without symptoms of overt stroke. As the etiology of SCI is unknown, we lack the means to identify children at risk for SCI, institute early therapy, or follow the success of therapy. The overall goal of this grant proposal is to identify diagnostic/prognostic plasma biomarkers of SCI in children ages 5-14 years with SCD. In our pilot studies, using a non-biased proteomic analysis of existing baseline plasma samples at enrollment in the Silent Infarct Transfusion (SIT) Trial from patients with or without SCI, we found differences in the protein profile and the presence of brain specific proteins in plasma of children with SCI. The SIT Trial represents a unique opportunity to: 1) extend these studies to serial plasma samples from study participants, which would be obtained as part of this proposal, but are not presently being obtained as part of the SIT Trial; 2) optimize sample procurement for deep proteomic analysis; and 3) assess biomarkers for prognostic value and therapeutic efficacy. We hypothesize that serial plasma samples optimized for proteomic studies from children with SCD and treated for SCI will contain diagnostic/prognostic biomarkers of SCI and treatment efficacy. The significance of the proposed studies is that identification of circulating markers of SCI could allow early intervention in these children, validate the efficacy of current therapy and provide insight into the design of new therapies. This proposal draws on the unique resources of the ongoing SIT Trial, the large and well phenotyped plasma samples in the SIT Trial Biologic Respository and the NHLBI Cardiovascular Proteomics Center at Johns Hopkins. In Specific Aim I, we will identify plasma biomarkers of SCI and evaluate differences in these biomarkers among 4 groups of patients: SCI patients randomly assigned to chronic transfusion (1) or standard care (2), patients without SCI (3), and patients with recent evidence of ischemic CNS injury (4), using state of the art, non-biased proteomic techniques (protein depletion, HPLC, ITRAQ and LC/MS/MS). In Specific Aim II, we will validate the efficacy of these biomarkers in predicting SCI and therapeutic response, using a combination of traditional western blotting and the development of high throughput multiplex antibody arrays. It is anticipated that these studies will provide new insights into the development of SCI and stroke in SCD and possibly ischemic CNS injury in other susceptible populations. This project has the potential to identify the protein biomarkers for the protection and evaluation of new and progressive silent cerebral infarcts. The identification of such circulating markers of SCI could allow early intervention in children who develop these lesions, help validate the efficacy of current therapy and provide insight into the design of new therapies. While we are studying a selected population of patients with a single gene disorder who develop silent cerebral infarction early in life, these results may generalize to the very large group of older individuals who develop silent cerebral infarctions as a presumed multi-factorial disorder (e.g., atherosclerosis, hypertension, diabetes, migraine, infection, other systemic diseases and aging), often associated with adverse outcomes such as dementia. Thus, the results of these studies could have a great deal of significance for public health in a variety of populations. (End of Abstract)

描述（由申请人提供）： 22％的镰状细胞疾病（SCD）发生静音脑梗塞（SCI），并与认知功能降低有关。根据定义，这些孩子具有与脑缺血或梗塞一致的MRI和病理证据，没有明显的中风症状。由于SCI的病因尚不清楚，因此我们缺乏识别有SCI风险，提早治疗或遵循治疗成功的儿童的手段。该赠款提案的总体目标是确定5-14岁儿童SCD儿童SCI的诊断/预后等离子体生物标志物。在我们的初步研究中，使用或没有SCI患者的无偏基线血浆样品对现有基线血浆样品进行了无偏的蛋白质组学分析，我们发现蛋白质谱和SCI儿童血浆中脑特异性蛋白的存在差异。 SIT试验代表了以下独特的机会：1）将这些研究扩展到研究参与者的串行等离子体样本，该研究将作为本提案的一部分获得，但目前尚未作为SIT试验的一部分获得； 2）优化样品采购以进行深度蛋白质组学分析； 3）评估生物标志物的预后价值和治疗功效。我们假设为SCD儿童和SCI治疗的蛋白质组学研究优化的连续等离子体样品将包含SCI的诊断/预后生物标志物和治疗功效。拟议的研究的重要性是，鉴定SCI循环标志物可以允许对这些儿童进行早期干预，验证当前疗法的疗效，并深入了解新疗法的设计。该建议借鉴了正在进行的SIT试验的独特资源，SIT试验生物学呼吸道中的大型且表现良好的血浆样本以及Johns Hopkins的NHLBI心血管蛋白质组学中心。 In Specific Aim I, we will identify plasma biomarkers of SCI and evaluate differences in these biomarkers among 4 groups of patients: SCI patients randomly assigned to chronic transfusion (1) or standard care (2), patients without SCI (3), and patients with recent evidence of ischemic CNS injury (4), using state of the art, non-biased proteomic techniques (protein depletion, HPLC, ITRAQ and LC/MS/MS）。在特定的目标II中，我们将使用传统的蛋白质印迹和高通量多重抗体阵列的结合来验证这些生物标志物在预测SCI和治疗反应方面的功效。可以预料，这些研究将为SCD中的SCI和中风发展以及其他易感人群中的缺血性中枢神经系统损伤提供新的见解。该项目有潜力识别蛋白质生物标志物，以保护和评估新的和进行性无声的脑梗塞。鉴定这种循环标记的SCI标记可以使早期干预患有这些病变的儿童，有助于验证当前疗法的疗效，并深入了解新疗法的设计。虽然我们正在研究一群单个基因疾病的患者的选定人群，这些患者在生命的早期就会发展出沉默的大脑梗塞，但这些结果可能会推广到非常大的老年人中，这些年龄段的人会作为一种假定的多因素疾病，例如，与其他因素障碍（例如，动脉粥样硬化，高血压，糖尿病，糖尿病，糖尿病，迁移，感染，其他系统性疾病），经常与其他系统疾病相关，经常与其他相关性。因此，这些研究的结果可能对各种人群的公共卫生具有很大的意义。 （抽象的结尾）