Predictors of Low-risk Phenotypes after Traumatic Brain Injury Incorporating Proteomic Biomarker Signatures.

结合蛋白质组生物标志物特征的创伤性脑损伤后低风险表型的预测因子。

基本信息

批准号：
10891945
负责人：
Holly Elaine Hinson
金额：
$ 22.4万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10891945
关键词：
Abbreviations Accounting Acute Acute Brain Injuries Admission activity Age Benign Blood Blood Vessels Brain Injuries Cause of Death Cell Adhesion Molecules Classification Clinical Clinical Data Clinical Research Clinical Trials Complement Complex Data Deterioration Development Disease model Enrollment Event Exclusion Criteria Glasgow Outcome Scale Goals Head Health Heterogeneity Holly Hospitals Hour Image Immune Immune response Injury Interleukin-6 Intervention Intracranial Hemorrhages Ion Transport Magnetic Resonance Imaging Mass Spectrum Analysis Measurable Measures Mediator Mentors Metabolism Methods Modeling Molecular Nervous System Trauma Neurologic Neurologist Oregon Outcome Outcome Measure Patient Care Patient Selection Patient risk Patients Peripheral Phenotype Population Proteins Proteomics ROC Curve Randomized Controlled Clinical Trials Research Project Grants Risk Science Series Signaling Protein Specific qualifier value Structure TBI treatment Technology Testing Therapeutic Clinical Trial Tranexamic Acid Traumatic Brain Injury Universities analog biomarker signature blood-based biomarker clinical phenotype clinical risk clinical translation clinically actionable cohort cytokine digital effective therapy high dimensionality immunoregulation improved inclusion criteria innovation insight mortality multidisciplinary novel patient oriented research patient stratification peripheral blood placebo group predictive modeling programs prospective proteomic signature response risk stratification sensor single molecule skills supervised learning

项目摘要

PROJECT SUMMARY Traumatic brain injury (TBI) is a leading cause of death in the US, and treatment options are limited. Therapeutic clinical trials in TBI have yielded disappointing results owing in part to the difficulty in accounting for clinically important heterogeneity within TBI. Early delivery of therapy is essential after TBI to reduce secondary brain injury, but unrestricted treatment of all brain injuries could be harmful. TBI stimulates a complex cascade of immunologic responses, both centrally and peripherally. These peripheral immune responses to TBI could serve as an early sensor of risk phenotype given the rapid, readily measurable response in the blood. An improved ability to risk-stratify patients on admission will streamline patient selection for aggressive interventions—such as invasive neuromonitoring—versus selection of those patients who can safely be observed reducing potential harms. Holly E Hinson, MD MCR is a Neurologist and Neurointensivist at Oregon Health and Science University where she cares for patients with severe acute brain injury. The objective of this application is to develop supervised learning models of actionable short- and long-term outcomes post-TBI and to interrogate if pre-specified immunoregulatory proteins add predictive power to the models over clinical features alone. Her central hypothesis is that immunoregulatory proteomic signatures improve our ability to classify a low-risk clinical phenotype after TBI. Dr. Hinson’s preliminary data suggest peripheral cytokine levels are associated with actionable clinical events acutely after TBI. The project employs a highly-sensitive, single molecule immunoarray (SIMOA) to detect immunoregulatory proteins complemented with an unbiased proteomic approach utilizing global discovery mass spectrometry. She will develop and assess a series of models incorporating proteomic signatures to classify: acute progressive intracranial hemorrhage (Aim 1A), acute neurologic deterioration (Aim 1B), and long-term outcomes measured by the 6-month Glasgow Outcome Scale (Aim 2). She will develop these models in a well-defined, clinical trial population (development set), and test their ability to correctly classify outcome in an independent, prospectively enrolled cohort at OHSU (test set). Under a multidisciplinary team of expert mentors, the project will generate new insights into low-risk phenotype recognition and outcome classification after acute TBI. The proposed patient-oriented research project will be enhanced by a structured didactic program in the principles of predictive modeling and patient phenotyping (including proteomics), which will provide Dr. Hinson with the critical skills she will need to conduct independent, innovative translational clinical research in the field of neurotrauma.

项目摘要创伤性脑损伤（TBI）是美国死亡的主要原因，治疗方案受到限制。 TBI的治疗性临床试验产生了令人失望的结果，部分原因是会计困难对于临床上重要的TBI异质性。在TBI之后，早期提供治疗至关重要次要脑损伤，但对所有脑损伤的无限制治疗可能是有害的。 TBI刺激a 免疫反应的复杂级联反应，无论是中央还是周边。这些外围免疫考虑到快速，易于测量的响应TBI可以作为风险表型的早期传感器血液中的反应。提高的患者在入院时风险分层的能力的提高将简化患者的选择为了进行积极的干预措施（例如侵入性神经监测），可以选择那些可以的患者可以安全地观察到减少潜在危害。医学博士Holly E Hinson是俄勒冈健康与科学大学的神经科医生和神经化学家她关心严重急性脑损伤的患者。该应用的目的是开发监督在TBI之后学习可操作的短期和长期结果的模型，并询问是否预先指定免疫调节蛋白仅在临床特征上为模型增加了预测能力。她的中央假设是免疫调节的蛋白质组学特征提高了我们对低风险临床分类的能力 TBI之后的表型。 Hinson博士的初步数据表明外围细胞因子水平与 TBI后急性可行的临床事件。该项目采用高度敏感的单分子免疫阵列（SIMOA）检测具有无偏蛋白质组学完成的免疫调节蛋白利用全球发现质谱法的方法。她将开发和评估一系列模型结合蛋白质组学特征进行分类：急性进行性颅内出血（AIM 1A），急性神经系统定义（AIM 1B）和长期结局通过6个月的格拉斯哥成果量表测量（目标2）。她将在定义明确的临床试验人群（开发集）和测试中开发这些模型他们在OHSU（测试集）的独立，可能招募的队列中正确分类结果的能力。在多学科的专家导师团队下，该项目将产生对低风险表型的新见解急性TBI后的识别和结果分类。拟议的面向患者的研究项目将是通过预测建模和患者表型的原理来增强结构化的教学计划（包括蛋白质组学），这将为Hinson博士提供她将需要的关键技能神经特征领域的独立，创新的翻译临床研究。