CRE rat for Psychiatric Disorders

用于治疗精神疾病的 CRE 大鼠

• 批准号: 8249029
• 负责人: Aron M Geurts
• 金额: $ 19.13万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249029
• 关键词: Acute; Addictive Behavior; Address; Affect; Affective; Aggressive behavior; Alleles; Animal Model; Animals; Anxiety; Area; Behavior; Behavioral; Biochemical; Biological Models; Brain; Brain Part; Breathing; Cells; Characteristics; Child Abuse; Commit; Complex; Crime; DNA Transposable Elements; Development; Discipline; Disease; Domestic Violence; Dopamine; Drug abuse; Embryonic Development; Employment; Enterobacteria phage P1 Cre recombinase; Enzymes; Failure; Feasibility Studies; Food; Future; Gene Transfer Techniques; Genes; Genetic; Genetic Determinism; Goals; Health Care Costs; Hormones; Human; Knock-in Mouse; Knock-out; Laboratory Rat; LacZ Genes; Lesion; Life; Mental Depression; Mental disorders; Modeling; Modification; Mood Disorders; Motivation; Mus; Mutation; Neurons; Neurotransmitters; Nucleus Accumbens; Organ; Pathology; Perinatal mortality demographics; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiologic Thermoregulation; Physiological; Pilot Projects; Play; Positive Reinforcements; Process; Psychological reinforcement; Rage; Rat Strains; Rattus; Research Personnel; Resources; Rewards; Role; Schizophrenia; Serotonin; Sleeping Beauty; Study models; Symptoms; System; Tamoxifen; Technology; Testing; Time; Tissues; Transgenic Animals; Transgenic Organisms; Ventral Tegmental Area; Work; Zinc Fingers; addiction; base; cost; design; dopaminergic neuron; drug of abuse; ecstasy; effective therapy; experience; family structure; fighting; gene function; genome sequencing; hindbrain; interest; knockout gene; neural circuit; neurophysiology; novel; nuclease; public health relevance; rat genome; recombinase; reproductive; response; socioeconomics; technology development; tool; trait

DESCRIPTION (provided by applicant): It is estimated that addiction and its associated costs: crime, domestic violence and child abuse, health care costs, and loss of employment and family structure, exceed half of a trillion dollars per year. Fighting addiction is not a matter of willpower, it is a battle to understand how drugs affect the brain and can permanently alter its function. One of the key limitations to understanding the cellular and genetic basis of a complex disease like addiction is the availability of good models to test hypotheses related to cells and genes and their functions. The laboratory rat is one model which has tremendous value because of its intensely studied physiological, biochemical, and behavioral characteristics and their genome sequence similarities to humans. More than 2000 genetic determinants of disease-related traits have been initially described in the rat, however, it has been difficult to precisely correlate specific genes with these traits because of limitations in technology for manipulating the rat genome. In the past 4 years, we have been developing new tools to close this technology gap. We have developed new and efficient ways of making transgenic rats using transposable elements which are highly reproducible and we were the first to apply zinc-finger nuclease (ZFN) technology to target and disrupt, or knock out, specific genes in the rat. These are two very important technologies that allow us to do many things, but more work is needed. Many times, knocking out a gene in the whole animal precludes studying its role in a particular cell or tissue because the gene is essential for early embryo development and so knocking it out causes the animal to die. In other cases, knocking out the gene in the whole animal doesn't allow one to distinguish what organ (or part of the brain, for example) the gene is functioning in to cause the disease. In this pilot/feasibility study, we propose to develop the next key technological step toward this goal - to be able to specifically disrupt genes in a particular cell or tissue at a particular time. We will develop transgenic rats which express an inducible CRE/loxP recombinase system in specific tissues. This system will allow us to create conditional knockout rats where we can control where and when a gene function is removed from a cell. We will focus brain neuron systems known to be important for studying addiction and behavior - the dopaminergic and serotonergic neurons. As a proof of principal that the system is working, we will knock out the gene that produces serotonin, a hormone that is important in the reward system of the brain and an integral player in addiction and other psychiatric disorders, specifically in neurons of the hindbrain. If successful, this approach will change the way we can approach genes, cells and diseases in the laboratory rat model to impact the socioeconomic burdens of addiction and drug abuse. PUBLIC HEALTH RELEVANCE: The key to developing effective therapies for the treatment of addiction and other psychiatric disorders is the identification of genes and the cells they work in to target new drugs and approaches. Lab rats are the preferred model for studying addiction by many resources, but the technology to study a particular gene by knocking out its function in a particular cell or tissue has not been demonstrated. This pilot and feasibility study aims to develop that technology in the lab rat so we can enable studies of specific genes and their roles in addictive behavior and other diseases.

描述（由申请人提供）：据估计，成瘾及其相关成本：犯罪，家庭暴力和虐待儿童，医疗保健费用以及就业和家庭结构损失，超过每年一半万亿美元的一半。战斗成瘾不是意志力的问题，而是一场了解药物如何影响大脑并可以永久改变其功能的斗争。理解复杂疾病（如成瘾）的细胞和遗传基础的关键局限性之一是可获得良好模型来检验与细胞和基因及其功能有关的假设。实验室大鼠是一种具有巨大价值的模型，因为其经过深入研究的生理，生化和行为特征及其与人类的基因组序列相似性。最初在大鼠中描述了2000多种与疾病相关性状的遗传决定因素，但是，由于操纵大鼠基因组的技术局限性，很难将特定基因与这些特征相关。在过去的四年中，我们一直在开发新的工具来缩小这一技术差距。我们已经开发了使用高度可重现的转座元素制造转基因大鼠的新方法，我们是第一个应用锌指核酸酶（ZFN）技术来靶向和破坏大鼠中的特定基因的人。这是两种非常重要的技术，使我们能够做很多事情，但是需要更多的工作。很多时候，在整个动物中敲出一个基因，无法研究其在特定细胞或组织中的作用，因为该基因对于早期胚胎发育至关重要，因此将其敲除出来会导致动物死亡。在其他情况下，淘汰整个动物中的基因不允许一个人（例如，大脑的一部分）区分该基因以引起疾病的作用。在这项试验/可行性研究中，我们建议朝着该目标发展下一个关键的技术步骤 - 能够在特定时间在特定细胞或组织中特异性破坏基因。我们将开发转基因大鼠，该大鼠在特定组织中表达可诱导的CRE/LOXP重组酶系统。该系统将使我们能够创建有条件的敲除大鼠，我们可以控制从单元格中删除基因函数的何时何地。我们将集中精神神经元系统，已知对于研究成瘾和行为很重要 - 多巴胺能和血清素能神经元。为了证明该系统正在起作用的主要证明，我们将淘汰产生5-羟色胺的基因，羟色胺是一种在大脑奖励系统中很重要的激素，并且是成瘾和其他精神疾病的整体参与者，尤其是在后脑神经元中。如果成功，这种方法将改变我们可以在实验室大鼠模型中处理基因，细胞和疾病的方式，以影响成瘾和药物滥用的社会经济负担。 公共卫生相关性：开发有效治疗成瘾和其他精神疾病的有效疗法的关键是鉴定基因及其针对新药和方法的细胞。实验室大鼠是许多资源研究成瘾的首选模型，但是尚未证明通过敲除特定细胞或组织中其功能来研究特定基因的技术。该试点和可行性研究旨在在实验室大鼠中开发该技术，因此我们可以研究特定基因及其在成瘾行为和其他疾病中的作用。