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A mouse model for genetic tracing to study stress responses

用于研究应激反应的基因追踪小鼠模型

基本信息

批准号：
8385998
负责人：
TSONWIN HAI
金额：
$ 22.88万
依托单位：
OHIO STATE UNIVERSITY
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：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385998
关键词：
A Mouse Acute Address Affect Alleles Area Biochemical Biological Cell Separation Cells Chronic Chronic stress Color Core Facility DNA Development Diet Disease Environment Erythrocytes Event Exploratory/Developmental Grant Fatty acid glycerol esters Fluorescence Future Gene Expression Genes Genetic Goals Green Fluorescent Proteins Half-Life Harvest Health Heart Human Injection of therapeutic agent Injury Label Lipopolysaccharides Liver Lung Malignant Neoplasms Modeling Molecular Mus Myocardial Infarction National Institute of Environmental Health Sciences Nerve Degeneration Nuclear Obesity Organ Play Process Production Proteins Reagent Reporter Research Research Personnel Risk Role Signal Transduction Site Sorting - Cell Movement Stress System Tamoxifen Testing Time Tissue Harvesting Toxin Transgenes Transgenic Mice Transgenic Organisms acute stress biological adaptation to stress cellular imaging design gene environment interaction innovation interest mouse model novel recombinase response tool web site

项目摘要

DESCRIPTION (provided by applicant): The environment to which humans are exposed often contains toxins and stress factors, which induce a variety of biological responses. These are gene-directed active processes; thus, how the cells respond and how genes and environments interact play an important role in disease development. The goal of this R21 is to establish a mouse model to study the biological responses to various environmental stresses. Designs and Utilities: The design is such that it will allow the researchers to trace and study both the cells under stress at the time of harvesting the tissues and the cells that were under stress in their past - long before harvesting. The mice will carry two transgenic alleles. 1. Stress-inducible Cre*: encodes a recombinase Cre fusion (Cre* for short), whose expression is turned on by a broad spectrum of stress signals, and 2. ROSA-Reporter: encodes Yellow Fluorescent Protein (YFP) preceded by Lox-STOP-Lox (LSL). The production of YFP is blocked by LSL and is possible only if the STOP is removed by active Cre*. This event physically and thus permanently alters the DNA, resulting in YFP production (green) to forever "mark" the cells. This allows one to "trace" the cells and determine their "fate. The Cre* is fluorescent (red); thus, the cells can be labeled red, if they are actively under stres (producing Cre*). With proper designs, one can distinguish cells that were once under stress in their past from those currently under stress. The fluorescent colors allow not only cell imaging but also cell isolation (by sorting) for biochemical and molecular analyses. Aim 1: To generate and characterize the stress-inducible Cre* transgenic mice. The transgenic construct will be generated using BAC recombineering and injected into pronucleus to make the mice. The mice will then be characterized for the expression and half-life of Cre* under acute and chronic stress paradigms. Aim 2: To generate and characterize the double transgenic mice. The stress-inducible Cre* mice will be crossed with the YFP reporter mice (available) to generate the double transgenic mice. The mice will then be analyzed to determine how tight the system is and how efficient the active Cre* is in removing the STOP. Innovation and Significance: The mouse model is novel for its ability to trace the fate of cells under various stresses, such as those induce liver injury, heart attack, neuronal degeneration, and cancer development. In addition, the proposed mouse model allows researchers to address issues regarding the transition from acute to chronic (or repeated) injuries¿an important but not well understood issue. The broad inducibility of Cre* makes the model an excellent tool to study environmentally-induced diseases - a special emphasis of NIEHS. PUBLIC HEALTH RELEVANCE: The goal of this R21 is to establish a novel mouse model to obtain new understanding of environmentally- induced diseases. The design is such that it will allow the researchers to trace and study both the cells under stress at the time of harvesting the tissues and the cells that were under stress in their past-long before harvesting. The successful establishment of the model will allow us to trace the fate of cells under a variety of stresses, such as those induce liver injury, heart attack, neuronal degeneration, and cancer development.

描述（由申请人提供）：