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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.

尽管有多条实验证据表明钙调蛋白参与了继发性骨质疏松症创伤性脑损伤(TBI)后的神经变性，对其下游作用知之甚少这些通路在局灶性和弥漫性脑损伤中可能有何不同。除了……之外阐明损伤大脑中钙蛋白的新靶点和细胞通路，该计划将评估抑制创伤后钙蛋白酶激活的几种新策略，包括增强钙调蛋白的活性，敲除钙蛋白酶I的异构体，并使用小分子抑制剂。该计划的总体目标动物核心(核心B)是为了促进该计划对Calain介导的神经病理和在局灶性和弥漫性脑外伤小鼠模型中钙蛋白酶抑制治疗策略的评估。为此，核心将履行三项具体职能，以支持计划目标：1)产生一致性、可预测的小鼠局部或弥漫性脑损伤将在项目1、2和3中进一步评估在核心C中，2)提供对大脑创伤后认知和运动功能的可靠、公正的评估- 用于评估减少创伤后Calain激活的策略的受伤和对照小鼠项目1、2和3)根据需要维持和扩大人类钙调蛋白的菌落过度表达的小鼠，钙蛋白酶I基因敲除的小鼠和亲环素D基因缺陷的小鼠在项目1和3以及核心C中使用通过这三个主要功能，动物核心将增加通过减少培训、人员和资源的冗余来提高方案的效率，并将加强项目和核心通过最大限度地减少变异性来直接比较数据的能力。此外，核心将提供盲目条件下的行为评估，并将提供集中管理转基因和基因敲除小鼠资源对该计划的科学利益至关重要。本组织的活动核心是成功完成该方案的科学目标所必需的。