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: 7761227
• 负责人: James F Casella
• 金额: $ 39.4万
• 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/7761227
• 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; Names; National Heart, Lung, and Blood Institute; Participant; Pathologic; Patients; Phase; Phenotype; Pilot Projects; Plasma; Plasma Proteins; Population; Principal Investigator; Proteins; Proteome; Proteomics; Public Health; Randomized; Research; Research Personnel; Resources; Risk; Sampling; Sampling Studies; Sickle Cell Anemia; Stream; Stroke; Structure; Symptoms; Systemic disease; Techniques; Technology; Therapeutic; Time; Transfusion; Treatment Efficacy; Validation; Western Blotting; abstracting; adverse outcome; arm; central nervous system injury; cognitive function; cohort; cost; design; insight; interest; patient population; prognostic; programs; 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）： 无症状性脑梗死（SCI）发生在22%的镰状细胞病（SCD）儿童中，并与认知功能下降有关。根据定义，这些儿童具有与脑缺血或梗死一致的MRI和病理学证据，没有明显的中风症状。由于脊髓损伤的病因不明，我们缺乏识别脊髓损伤高危儿童的方法，缺乏早期治疗方法，也缺乏跟踪治疗成功与否的方法。这项拨款提案的总体目标是确定5-14岁SCD儿童SCI的诊断/预后血浆生物标志物。在我们的初步研究中，使用无偏倚的蛋白质组学分析，对参加无症状输血（SIT）试验的SCI或非SCI患者的现有基线血浆样本进行分析，我们发现SCI儿童血浆中的蛋白质谱和脑特异性蛋白质存在差异。SIT试验代表了一个独特的机会：1）将这些研究扩展到研究参与者的系列血浆样本，这些样本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）优化用于深度蛋白质组学分析的样本采购; 3）评估生物标志物的预后价值和治疗疗效。我们假设，从SCD儿童和SCI治疗的蛋白质组学研究优化的系列血浆样本将包含SCI和治疗效果的诊断/预后生物标志物。拟议研究的意义在于，确定SCI的循环标志物可以允许对这些儿童进行早期干预，验证当前治疗的有效性，并为新疗法的设计提供见解。该提案借鉴了正在进行的SIT试验的独特资源，SIT试验生物学储存库和约翰霍普金斯NHLBI心血管蛋白质组学中心的大量和良好表型血浆样本。在具体目标I中，我们将确定SCI的血浆生物标志物，并评估4组患者中这些生物标志物的差异：SCI患者被随机分配到长期输血组（1）或标准治疗组（2）、无SCI患者（3）和近期有缺血性CNS损伤证据的患者（4），使用最新技术水平、无偏倚蛋白质组学技术（蛋白质耗竭、HPLC、ITRAQ和LC/MS/MS）。在Specific Aim 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开发相结合来验证这些生物标志物在预测SCI和治疗反应中的功效。预计这些研究将为SCD中SCI和卒中的发展以及其他易感人群中可能的缺血性CNS损伤提供新的见解。该项目有可能鉴定用于保护和评估新发和进行性无症状脑梗死的蛋白质生物标志物。这些SCI循环标志物的鉴定可以允许对发展这些病变的儿童进行早期干预，帮助验证当前治疗的有效性，并为新疗法的设计提供见解。虽然我们正在研究在生命早期发展为无症状脑梗死的单基因疾病患者的选定人群，但这些结果可以推广到发展为假定的多因素疾病（例如，动脉粥样硬化、高血压、糖尿病、偏头痛、感染、其他全身性疾病和衰老），通常与诸如痴呆的不良结果相关。因此，这些研究的结果可能对各种人群的公共卫生具有重大意义。(End摘要）