exRNA signatures Predict Outcomes after brain injury

exRNA 特征预测脑损伤后的结果

• 批准号: 8710365
• 负责人: P. David ADELSON
• 金额: $ 49.74万
• 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/8710365
• 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)： 创伤性脑损伤，无论是对大脑的直接损伤，还是作为缺血性或出血性脑梗塞的后遗症，都与相当高的发病率有关， 死亡率和患者和医疗系统的成本。出血性脑梗塞(如动脉瘤性蛛网膜下腔出血和脑室出血)是动脉破裂的罕见但破坏性的并发症。尽管付出了很大的努力，但蛛网膜下腔出血(ASAH)或脑室出血(IVH)患者的预后几乎没有改善。考虑到这些脑损伤的可预测的时间过程，它们是识别生物标记物的理想候选者。一个检测高危患者的生物标记物和延迟性神经功能障碍的预后指标将极大地改善目前的治疗方法，并增加我们对潜在病理事件的理解。这一信息将立即导致新的治疗策略的实施。过去几年的研究已经确定细胞外RNA(ExRNA)是生物标记物的潜在来源。新技术，如下一代测序(NGS)，使灵敏和定量地分析临床可获得的生物液(如脑脊液和血浆)中的少量RNA成为可能。在这笔赠款的头两年，我们建议对ASAH患者的脑脊液和血浆以及出生时患有IVH的早产儿的脑脊液和脑脊液中的exRNA(miRNA和总RNA)进行测序。每天收集ASAH样本~可用的样本量将使我们不仅能够对包括miRNAs在内的总RNA进行测序，还将使我们能够在这笔赠款的第3-5年探索独特的浓缩策略~我们将检测与脑脊液和血浆中的微囊相关的特定RNA。我们有这些患者的日常临床评估以及他们的结果(总共25名受试者)。我们将使用这些样本来识别预测血管痉挛发生和延迟性神经功能障碍严重程度的RNA标志物。我们还每隔一天从患有III-IV级IVH的早产儿身上采集脑脊液和血浆样本，这些早产儿设置了储血池来排空血液和 脑脊液过多。我们也有婴儿的临床结果，无论他们是否 发生脑积水、需要永久分流，以及对发育迟缓或残疾的18个月评估。在3-5年，我们将继续与我们的临床合作伙伴合作收集样本。届时，我们将从我们的发现平台，具有高测序深度的Illumina HiSeq 2000切换到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更快的流体、成像和缩短的运行时间进行验证，而不会改变发现和验证阶段之间的化学成分。