Animal

动物

基本信息

批准号：
7288123
负责人：
KATHRYN E SAATMAN
金额：
$ 14.68万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7288123
关键词：
Adult Animals Behavior assessment Behavioral Blinded Brain Brain Injuries Breeding Calpain Calpain I Cognitive Condition Craniocerebral Trauma Cultured Cells Data Diffuse Drops Evaluation Female Generations Genotype Goals Human Human Resources Individual Injury Investigation Knock-out Knockout Mice Life Literature Maintenance Mediating Modeling Monitor Motor Mus Nerve Degeneration Neurologic Dysfunctions Operative Surgical Procedures Pathway interactions Patient currently pregnant Performance Procedures Process Program Efficiency Protein Isoforms Protein Overexpression Reagent Research Personnel Resources Schedule Survivors Testing Therapeutic Time Tissue Harvesting Training Transgenic Mice Transgenic Organisms Traumatic Brain Injury Weight brain pathway calpastatin cellular targeting cognitive function cohort controlled cortical impact cyclophilin D functional outcomes grasp in vivo inhibitor/antagonist injured insight interest memory retention morris water maze mouse model neuropathology novel novel strategies pre-clinical programs research study small molecule

项目摘要

Although multiple lines of experimental evidence implicate calpains in the process of secondary neurodegeneration following traumatic brain injury (TBI), little is understood about the downstream actions of calpains in the injured brain, and how these pathways might differ in focal and diffuse TBI. In addition to elucidating novel targets and cellular pathways for calpains in the injured brain, the Program will evaluate several novel strategies to inhibit posttraumatic calpain activation, including enhancing activity of calpastatin, knocking out the calpain I isoform, and administering small molecule inhibitors. The overall goal of the Animal Core (Core B) is to facilitate the Program's investigations of calpain-mediated neuropathology and evaluations of calpain inhibitory therapeutic strategies in mouse models of focal and diffuse TBI. To thisend, the Core will perform three specific functions in support of Program objectives: 1) produce consistent, predictable focal or diffuse traumatic brain injuries in mice to be further evaluated in Projects 1, 2, and 3 and in Core C, 2) provide reliable, unbiased assessments of posttraumatic cognitive and motor function in brain- injured and control mice for evaluation of strategies to reduce posttraumatic calpain activation pursued in Projects 1, 2 and 3, and 3) maintain and expand, as necessary, colonies of human calpastatin overexpressing mice, calpastatin deficient mice, calpain I knockout mice and cyclophilin D deficient mice for use in Projects 1 and 3 and Core C. Through these three major functions, the Animal Core will increase the efficiency of the Program by reducing redundancy in training, personnel and resources, and will enhance the ability of Projects and Cores to directly compare data by minimizing variability. In addition, the Core will provide behavioral assessments under blinded conditions and will provide centralized management of transgenic and knockout mouse resources vital to the Program's scientific interests. The activities of the Core are essential to the successful completion of the scientific goals of the Program.

尽管多种实验证据暗示了在次级过程中神经退行性脑损伤（TBI）后的神经变性，几乎没有理解受伤的大脑中的钙蛋白酶以及这些途径在局灶性和弥漫性TBI中的差异。此外阐明了受伤大脑中钙的新型靶标和细胞途径，该程序将评估几种抑制创伤后钙蛋白酶激活的新型策略，包括增强钙蛋白酶的活性，拆除钙蛋白酶I的同工型，并施用小分子抑制剂。总体目标动物核心（核心B）是为了促进该计划对Calpain介导的神经病理学和在局灶性和弥漫性TBI小鼠模型中评估钙蛋白酶抑制性治疗策略。为此，核心将执行支持程序目标的三个特定功能：1）产生一致，在项目1、2和3中进一步评估小鼠中可预测的局灶性或弥漫性脑损伤，并且在核心中，2）在脑部创伤后认知和运动功能中提供可靠的，无偏见的评估受伤和控制小鼠以评估减少创伤后钙蛋白酶激活的策略项目1、2和3，以及3）根据必要过表达的小鼠，钙蛋白酶缺乏小鼠，钙蛋白酶I基因敲除小鼠和环磷脂D缺乏小鼠在项目1和3和CoreC中使用。通过这三个主要功能，动物核心将增加通过降低培训，人员和资源的冗余，该计划的效率，并将增强项目和核心通过最小化变异性直接比较数据的能力。此外，核心将在盲人条件下提供行为评估，并将提供集中的管理转基因和淘汰小鼠资源对该计划的科学利益至关重要。活动的活动核心对于成功完成该计划的科学目标至关重要。