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Novel transgenic mice for tracing and electrophysiology of stressed neurons

用于应激神经元追踪和电生理学的新型转基因小鼠

基本信息

批准号：
8835696
负责人：
TSONWIN HAI
金额：
$ 2.94万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8835696
关键词：
Acute Address Affect Afferent Neurons Alleles Basic Science Behavior assessment Biochemical Genetics Brain Concussion Breeding Cell physiology Cells Cellular Stress Cellular Stress Response Characteristics Chimeric Proteins Chronic Core Facility Demyelinations Disease Electrophysiology (science)Event Exhibits Gated Ion Channel Gene Expression Generations Genes Genetic Goals Hand Health Image In Vitro Individual Injection of therapeutic agent Injury Ischemia Knockout Mice Label Lasers Life Light Long-Term Effects Microscopy Modeling Motor Neurons Mus Nerve Crush Neurologic Neurons Nuclear Operative Surgical Procedures Optics Pain Pathology Peripheral Nervous System Physiological Play Population Process Production Promoter Regions Proteins Reporter Research Signal Transduction Stress Synapses System Tamoxifen Time Tissues Transgenes Transgenic Mice Transgenic Organisms Trauma Venus activating transcription factor 3 analog base biological adaptation to stress cell injury chemotherapeutic agent chronic pain in vivo injured innovation light gated mouse model nervous system disorder neurological pathology novel optogenetics recombinase response response to injury stressor tissue fixing tool

项目摘要

DESCRIPTION (provided by applicant): Numerous neurological diseases and pathologies include, or are hypothesized to include, cellular injury and/or stress as part of the mechanism. Experimental approaches to examine these mechanisms, or even determine if they are indeed at play in certain conditions, are generally limited. They include post-mortem analyses of known stress-response genes/molecules, in vivo pharmacological manipulations which are often systemic, or functional assessments/manipulations which often cannot separate stressed from non-stressed neurons. Ideally, it would be possible to determine, a priori on a cell-by-cell basis, which neurons in a mixed population were exhibiting a cell-stress response. Further, since some stress responses, or at least some components of the stress response, are only transiently expressed even though the overall stress responses may have a cumulative effect on the cell, it would be highly useful to have an a priori indication of which neurons had exhibited a stress response at some point in the past. It would also be highly useful to be able to selectively assess the cellular and inter-cellular functionality of the stressed neurons. To these ends we propose to generate new functional-reporter transgenic mouse lines which will incorporate these characteristics. The reporters will be driven by the promoter region of Activating Transcription Factor 3 (ATF3), a "hub" protein involved in a variety of cellular stress responses. Generation of the mice will be via BAC-transgenes in order to preserve function of the native ATF3 alleles, which are necessary for certain cellular processes. The BAC transgene with the ATF3 locus will drive production of the light-gated ion channel channelrhodopsin-2 (ChR2) fused to a fluorescent protein. One model will have the reporters produced in an analogue fashion (i.e., to reflect native ATF3 expression). A second model will use an inducible Cre-recombinase system to permanently "switch-on" reporter production, thus allowing, at any later time, identification of neurons that previously expressed a stress response. These functional-reporter models will allow offline anatomical assessments, FACS or laser-capture separations, fate-tracing of previously-stressed neurons, and in vivo or in vitro functional assessments specifically of stressed neurons (i.e., those expressing ChR2).

描述（由申请人提供）：许多神经系统疾病和病理包括或假设包括细胞损伤和/或应激作为机制的一部分。检验这些机制，甚至确定它们是否确实在某些条件下起作用的实验方法通常是有限的。它们包括对已知应激反应基因/分子的死后分析，通常是系统性的体内药理学操作，或者通常不能将应激神经元与非应激神经元分开的功能评估/操作。理想情况下，有可能在一个细胞一个细胞的基础上先验地确定，