Bioinformatics For Translational Spinal Cord Injury Research

描述(申请人提供)：脊髓损伤(SCI)产生一种多方面的综合征，其特征是失去活动能力、膀胱、肠道和性功能丧失、病理性疼痛和丧失自主性。在过去的20年里，我们在动物模型上模拟人类脊髓损伤的许多特征的能力取得了重大进展，但很少有实验疗法从实验室移植到人类患者身上。翻译的一个主要障碍是缺乏关于SCI的哪些结果指标在不同的实验室、菌株、损伤类型和物种之间具有可比性的信息。确定这些重要的共同成果指标是拟议项目的一个主要目标。我们假设，实验性脊髓损伤会产生一种生物行为综合征，不仅反映在一个结果上，而且在许多不同的结果上都有一致的模式。许多实验性脊髓损伤研究人员在使用同一实验对象的几个结果来评估实验疗法时，隐含地假设了这一观点。然而，这些数据还没有使用复杂的多变量信息处理程序进行分析，这些程序旨在检测、测量和量化复杂数据集中的疾病模式。通过汇集多个实验室的数据并进行跨物种比较，我们将利用现有的实验数据来确定可用于评估跨物种SCI机制的SCI通用指标。我们提出了以下目标：1)建立现有实验啮齿动物和灵长类SCI研究数据的池数据库，为知识发现和跨不同结果和实验模型的多变量量化提供平台。我们将从5个主要SCI研究中心的数据开始，为以后其他研究小组的贡献提供一个框架。2)识别啮齿动物脊髓损伤模型中的证候指标，使用临床研究人员经常使用的多变量技术来定义和测量复杂的疾病状态。3)确定啮齿动物模型中的哪些多变量结局模式对分级损伤的影响最敏感，以及哪些对随时间的变化最敏感，目的是提高敏感性并简化治疗干预测试。4)确定在非人类灵长类动物中，哪些多变量结果模式对脊髓损伤和随时间的恢复的影响最敏感，为这一有价值的临床前模型中的治疗试验提供关于最敏感结果的重要信息。5)对啮齿动物和灵长类SCI数据进行翻译多变量比较，以确定哪些结果模式在实验模型中翻译得最好，哪些是物种和模型特定的，为未来与人类数据的多变量比较奠定了基础。这代表了实验性SCI领域的一个新方向，我们期待这种方法有助于定义跨物种可比较的结果指标，促进翻译SCI研究。 与公共卫生相关：拟议的项目重点关注脊髓损伤，这是一种毁灭性的综合征，在美国影响着大约25万人，每年给国家造成近100亿美元的医疗保健和生产力损失。受伤的人会受到行动能力丧失、膀胱、肠道和性功能丧失、病理性疼痛和自主性丧失的困扰。这些变化大大降低了受伤个人及其亲人的生活质量。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) produces a multifaceted syndrome characterized by loss of mobility, loss of bladder, bowel and sexual function, pathological pain, and a loss of autonomy. The past 20 years have seen significant progress in our ability to emulate many features of human SCI in animal models, yet few experimental therapies have translated from the laboratory to human patients. One major obstacle to translation is the lack of information about which outcome metrics for SCI are comparable across different laboratories, strains, types of injuries, and species. Identification of these important common outcome metrics is a major goal of the proposed project. We hypothesize that experimental SCI produces a bio-behavioral syndrome that is reflected not by only one outcome, but rather consistent patterns across many different outcomes. This view is implicitly assumed by many experimental SCI researchers when they evaluate experimental therapeutics using several outcomes from the same experimental subjects. However these data have not been analyzed using sophisticated multivariate information processing procedures which are designed to detect, measure, and quantify disease patterns in complex datasets. By pooling data from several laboratories and making cross- species comparisons, we will leverage existing experimental data to identify common metrics of SCI that can be used for evaluating mechanism of SCI that translate across species. We propose the following Aims: 1) Build a pooled database of existing experimental rodent and primate SCI research data to provide a platform for knowledge discovery and multivariate quantification across diverse outcomes and experimental models. We will start with data from 5 major SCI research centers to provide a framework for later contributions from other research groups. 2) Identify syndrome measures in rodent SCI models, using the same multivariate techniques often used by clinical researchers to define and measure complex disease states. 3) Identify which multivariate outcome patterns in rodent models are most sensitive to the effects of graded injury and which are most sensitive to change over time, with the goal of improving sensitivity and streamlining testing of therapeutic interventions. 4) Identify which multivariate outcome patterns in non-human primates are most sensitive to the effects of SCI and recovery over time, providing important information about the most sensitive outcomes for therapeutic testing in this valuable preclinical model. 5) Make translational multivariate comparisons of rodent and primate SCI data to identify which outcome patterns best translate across experimental models and which are species- and model-specific, setting the stage for future multivariate comparisons to human data. This represents a new direction for the field of experimental SCI and we expect this approach to help define outcome metrics that are comparable across species, facilitating translational SCI research. PUBLIC HEALTH RELEVANCE: The proposed Project focuses on spinal cord injury, a devastating syndrome, affecting approximately 250,000 people in the United States, and costing the nation almost 10 billion dollars per year in healthcare and loss-of- productivity. Injured individuals are plagued by loss of mobility; loss of bladder, bowel and sexual function; pathological pain; and a loss of autonomy. These changes profoundly reduce the quality of life for injured individuals and their loved ones.