A Pre-Clinical Model of TBI Heterogeneity

 描述（由申请人提供）：TBI异质结的临床前模型。大多数创伤性脑损伤被认为是轻微的。轻度TBI（mTBI）难以诊断， 尽管最近在公众意识和临床管理方面取得了进展，但mTBI（或脑震荡）在体育运动、军队和普通人群中仍是一个持续存在的问题。为了进一步了解损伤机制，识别更敏感的诊断工具，并开始深入研究神经退行性变的明显风险，需要改进临床前实验室研究。考虑到患者的异质性和生理学特征， TBI的复杂性尽管进行了数十年的基础研究，但将潜在的治疗方法从动物身上成功地转化为患者身上的效果非常差。在临床前研究中未捕获临床群体异质性，严重限制了验证动物模型作为可靠研究替代物的能力。本研究的长期目标是使用双向系统方法改善实验室到诊所的翻译。本R21研究提案的总体目标是在临床前动物研究中反映mTBI患者人群的异质性，并使用基于信息学的分析来确定有助于损伤反应的特征。中心假设是，动物异质性的系统机构将导致更可重复和更稳健的临床前TBI研究和临床相关风险因素的出现。实验目的是：1）开发用于mTBI的临床前实验设计，其选择患者相关变量（性别、年龄、遗传多样性、先前的mTBI和慢性应激）并使用分层随机化将它们应用于异质大鼠群体;和2）使用异质大鼠群体在mTBI后急性评估急性神经反应、平衡、工作记忆和生物标志物特征。信息学工具将取代传统的多元统计学，以提取损伤反应的共同特征，对其进行分类，并建立预测知识模型。将测试几个嵌入的假设，以检查作为动物性别、年龄、品系、先前mTBI和慢性应激的函数的对mTBI的反应。预计由于稳健的实验设计和基于知识的模型，数据之间会出现意想不到的关系。这里提出的实验平台是新颖的，如果成功的话，可以作为其他研究的模板。解决患者异质性和临床相关的急性结局指标非常重要，并将增加对mTBI复杂性的理解。

 DESCRIPTION (provided by applicant): A Pre-Clinical Model of TBI Heterogeneity. The majority of traumatic brain injuries are considered mild. Mild TBI (mTBI) is difficult to diagnose, and despite recent progress in public awareness and clinical management, mTBI (or concussion) is a persistent problem in sports, the military, and in the general population. In order to further understand injury mechanisms, identify more sensitive diagnostic tools, and begin to delve into the apparent risk for neurodegeneration, there is a need to improve pre-clinical laboratory studies. This is no easy task given patient heterogeneity and the physiological complexity of TBI. Despite decades of basic research, successful translation of potential treatments from animal to patients is extremely poor. Clinical population heterogeneity is not captured in pre-clinical studies, gravely limiting the ability to validate animal models as reliabl research surrogates. The long-term goal of this research is to improve lab-to-clinic translation using a bi- directional systems approach. The overall goal of this R21 Research Proposal is to reflect the heterogeneity of the mTBI patient population in a pre-clinical animal study and use informatics-based analysis to determine features that contribute to the injury response. The central hypothesis is that systematic institution of animal heterogeneity will result in more reproducible and robust pre- clinical TBI studies and the emergence of clinically relevant risk factors. The experimental aims are: 1) Develop a pre-clinical experimental design for mTBI that selects patient-relevant variables (gender, age, genetic variety, previous mTBI, and chronic stress) and applies them to a heterogeneous rat population using stratified randomization; and, 2) Assess acute neurological response, balance, working memory, and biomarker signature acutely following mTBI using a heterogeneous rat population. Informatics tools will be used in place of traditional multivariate statistics to extract common features of the injury response, classify them, and build predictive knowledge models. Several imbedded hypotheses will be tested to examine the response to mTBI as a function of animal sex, age, strain, previous mTBI, and chronic stress. It is expected that unanticipated relationships among the data will emerge as a result of the robust experimental design and knowledge-based model. The experimental platform presented here is novel and, if successful, can be used as a template for other studies. Addressing patient heterogeneity and clinically relevant acute outcome measures is highly significant and will increase understanding of the complexity of mTBI.