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)： 无症状性脑梗塞(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，这些儿童有符合脑缺血或脑梗塞的核磁共振和病理证据，没有明显的中风症状。由于脊髓损伤的病因尚不清楚，我们缺乏识别有脊髓损伤风险的儿童、进行早期治疗或跟踪治疗成功的手段。这项赠款提案的总体目标是在5-14岁的SCD儿童中确定SCI的诊断/预后血浆生物标志物。在我们的先导性研究中，我们对参加静默脑梗塞输注(SIT)试验的现有基线血浆样本进行了无偏倚的蛋白质组学分析，发现患有或不患有脊髓损伤的患者的蛋白质谱和血浆中脑特异性蛋白质的存在存在差异。SIT试验代表着一个独特的机会：1)将这些研究扩展到来自研究参与者的连续血浆样本，这些样本将作为这项建议的一部分获得，但目前还没有作为SIT试验的一部分获得；2)优化样本采购以进行深入的蛋白质组学分析；以及3)评估生物标记物的预后价值和治疗效果。我们假设，针对SCD儿童的蛋白质组学研究和SCI治疗优化的系列血浆样本将包含SCI的诊断/预后生物标志物和治疗效果。这项研究的意义在于，识别脊髓损伤的循环标志物可以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洞察力。这项建议利用了正在进行的SIT试验的独特资源、SIT试验生物储存库和约翰霍普金斯大学NHLBI心血管蛋白质组学中心的大量和良好的表型血浆样本。在特定的目标I中，我们将利用最新的、无偏见的蛋白质组学技术(蛋白质耗竭、高效液相色谱、iTRAQ和LC/MS/MS)，鉴定脊髓损伤的血浆生物标志物，并评估这些生物标志物在4组患者中的差异：SCI患者随机分配到慢性输液组(1例)或标准治疗组(2例)，非SCI组(3例)，以及最近发现缺血性中枢神经系统损伤的患者(4例)。在特定的目标II中，我们将结合传统的蛋白质印迹和高通量多重抗体阵列的开发，验证这些生物标记物在预测脊髓损伤和治疗反应方面的有效性。预计这些研究将为SCD的脊髓损伤和卒中的发展以及其他易感人群中可能的缺血性中枢神经系统损伤提供新的见解。该项目有可能确定用于保护和评估新的和进展性无症状性脑梗塞的蛋白质生物标志物。识别这种脊髓损伤的循环标志物可以对发生这些损害的儿童进行早期干预，有助于验证当前治疗的有效性，并为新疗法的设计提供洞察力。虽然我们正在研究一组患有单基因疾病的患者，他们在生命早期患上无症状性脑梗塞，但这些结果可能推广到非常大的一组老年人，他们患上无症状性脑梗塞是一种假定的多因素障碍(例如，动脉粥样硬化、高血压、糖尿病、偏头痛、感染、其他全身疾病和衰老)，通常与痴呆症等不良后果有关。因此，这些研究的结果可能对不同人群的公共卫生具有很大的意义。(摘要结束)