Bioinformatics For Translational Spinal Cord Injury Research

描述（由申请人提供）：脊髓损伤（SCI）产生多方面的综合征，其特征是活动能力丧失，膀胱、肠道和性功能丧失，病理性疼痛和自主性丧失。在过去的20年中，我们在动物模型中模拟人类SCI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转化为人类患者。翻译的一个主要障碍是缺乏关于SCI结果指标在不同实验室、菌株、损伤类型和物种之间可比较的信息。确定这些重要的公共结果度量是拟议项目的主要目标。我们假设，实验性脊髓损伤产生的生物行为综合征不仅反映在一种结果上，而且反映在许多不同结果的一致模式上。许多实验性SCI研究人员在使用来自同一实验对象的几个结果来评估实验性治疗方法时隐含地假设了这一观点。然而，这些数据尚未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。通过汇集来自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SCI的通用指标，这些指标可用于评估SCI跨物种转化机制。我们提出以下目标：1)建立现有啮齿类和灵长类动物SCI实验数据的汇集数据库，为跨结果和实验模型的知识发现和多元量化提供平台。我们将从5个主要SCI研究中心的数据开始，为其他研究小组的后续贡献提供一个框架。2)确定啮齿动物脊髓损伤模型的综合征测量，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哪些多变量结果模式对分级损伤的影响最敏感，哪些对随时间变化最敏感，以提高敏感性和简化治疗干预措施的测试。4)确定非人类灵长类动物中哪些多变量结果模式对脊髓损伤的影响和随时间的恢复最敏感，为这个有价值的临床前模型的治疗试验提供最敏感结果的重要信息。5)对啮齿类动物和灵长类动物的SCI数据进行多变量翻译比较，以确定哪些结果模式在不同的实验模型中最好地翻译，哪些是特定于物种和模型的，为未来与人类数据的多变量比较奠定基础。这代表了实验SCI领域的一个新方向，我们期望这种方法有助于定义跨物种可比较的结果指标，促进SCI的转化研究。

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.