exRNA signatures Predict Outcomes after brain injury

exRNA 特征预测脑损伤后的结果

• 批准号: 8581741
• 负责人: P. David ADELSON
• 金额: $ 50万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581741
• 关键词: Adult; Aneurysmal Subarachnoid Hemorrhages; Biological Assay; Biological Markers; Blood; Brain; Brain Injuries; Caring; Cerebrospinal Fluid; Chemistry; Childhood; Clinical; Clinical assessments; Collaborations; Collection; Creation of ventriculo-peritoneal shunt; Data; Data Collection; Detection; Development; Developmental Delay Disorders; Developmental Disabilities; Diagnostic; Disease Outcome; Enrollment; Event; Excision; Exhibits; Gene Expression Profile; Grant; Healthcare Systems; Hemorrhage; Hydrocephalus; Image; Infarction; Injury; Institutes; Lead; Medical Records; MicroRNAs; Monitor; Morbidity - disease rate; Multivariate Analysis; Neurologic; Neurological outcome; Outcome; Pathway interactions; Patients; Performance; Phase; Plasma; Population; Premature Infant; Process; Prognostic Marker; RNA; RNA marker; Research; Risk; Running; Rupture; Sampling; Sensitivity and Specificity; Sequence Analysis; Severities; Severity of illness; Shunt Device; Signal Transduction; Small RNA; Source; Techniques; Testing; Time; Trauma; Traumatic Brain Injury; Validation; Vasospasm; Ventricular; Visit; cost; extracellular; follow-up; improved; infant outcome; innovation; intraventricular hemorrhage; mortality; new technology; next generation sequencing; novel therapeutics; public health relevance; research clinical testing; sample collection; treatment strategy

DESCRIPTION (provided by applicant): Traumatic brain injury, both from direct trauma to the brain and as a sequela of ischemic or hemorrhagic infarction are associated with a significant rate of morbidity, mortality and cost to both patients and the healthcare system. Hemorrhagic infarcts (such as aneurysmal subarachnoid hemorrhage and intraventricular hemorrhage) are rare but devastating complications of arterial rupture. Despite significant effort, there has been little improvement in the outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH) or intraventricular hemorrhage (IVH). Given the predictable temporal course of these brain injuries, they are ideal candidates for biomarker identification. A biomarker for detection o 'at risk' patients and a prognostic indicator of delayed neurological deficit would vastly improve current treatments and increase our understanding of underlying pathological events. This information would immediately lead to the implementation of new therapeutic strategies. Research over the last several years has identified extracellular RNAs (exRNA) as a potential source of biomarkers. New technology, such as next generation sequencing (NGS), has made it possible to sensitively and quantitatively assay small amounts of RNA contained in clinically attainable volumes of biofluids such as CSF and blood plasma. In the first two years of this grant, we propose to sequene the exRNA (miRNA and total RNA) from both the CSF and plasma of patients who present with aSAH and the plasma and CSF from premature infants born with IVH. aSAH samples were collected daily~ the volume of sample available will allow us not only to sequence the total RNA including miRNAs, but will permit us to explore unique enrichment strategies in years 3-5 of this grant~ we will examine specific RNAs associated with microvesicles in both CSF and plasma. We have both the daily clinical evaluations of these patients as well as their outcomes (25 subjects in all). We will use these samples to identiy RNA markers that predict onset of vasospasm and the severity of delayed neurological deficits. We also have CSF and plasma samples collected every other day from premature infants with grade III-IV IVH that had reservoirs put in place to evacuate blood and excess CSF. We also have the clinical outcomes from the infants, whether or not they developed hydrocephalus, the need for a permanent shunt, and an 18 month assessment of developmental delays or disabilities. In years 3-5, we will continue to collect samples in collaboration with both of our clinical partners. At that time, we will switch from our discovery platform, the Illumina HiSeq 2000 that has high depth of sequencing coverage, to the Illumina MiSeq for validation. Once the discovery phase is complete and potential biomarkers identified, validation can be carried out on the MiSeq's faster fluidics, imaging, and shortened run times without changing chemistries between the discovery and validation phases.

描述（由申请人提供）： 从直接创伤到大脑，以及作为缺血性或出血性梗死的续集，脑部损伤都与发病率显着相关， 患者和医疗保健系统的死亡率和成本。 出血性梗塞（例如动脉瘤性蛛网膜下腔出血和脑室内出血）是罕见但动脉破裂的毁灭性并发症。 尽管付出了巨大的努力，但动脉瘤性蛛网膜下腔出血（ASAH）或脑室内出血（IVH）的患者的结局几乎没有改善。鉴于这些脑损伤的可预测时间过程，它们是生物标记鉴定的理想候选者。一种用于检测风险的生物标志物和延迟神经缺陷的预后指标，将大大改善当前治疗方法，并提高我们对潜在病理事件的理解。 这些信息将立即导致实施新的治疗策略。 在过去的几年中，研究将细胞外RNA（EXRNA）确定为生物标志物的潜在来源。 新技术，例如下一代测序（NGS），使得在临床上可达到的生物流体（例如CSF和血浆）中敏感和定量测定少量RNA。 在这笔赠款的前两年中，我们提议将EXRNA（miRNA和Total RNA）序列化的CSF和血浆，这些患者与ASAH，血浆以及患有IVH的早产儿的血浆和CSF的患者的血浆隔离。每天收集ASAH样品〜可用的样品数量不仅可以使包括miRNA在内的总RNA顺序，还可以使我们能够探索这笔赠款3 - 5年的独特富集策略。我们对这些患者的每日临床评估及其结果进行（共25名受试者）。 我们将使用这些样品来识别预测血管痉挛发作和延迟神经缺陷的严重程度的RNA标记。我们还每隔一天收集一次CSF和血浆样本，该婴儿从患有IIII-IV级IVH的早产儿中收集，这些级别的储藏室就位以疏散血液和 多余的CSF。 我们也有来自婴儿的临床结果 开发了脑积水，对永久分流的需求以及对发育延迟或残疾的18个月评估。在3 - 5年内，我们将继续与两个临床合作伙伴合作收集样品。当时，我们将从我们的发现平台，即测序覆盖范围高的Illumina Hiseq 2000转到Illumina Miseq进行验证。 一旦发现阶段完成并确定了潜在的生物标志物，就可以对Miseq的更快的流体，成像和缩短运行时间进行验证，而不会在发现和验证阶段之间改变化学成分。