Project 3: Functional Studies of Novel Candidate Genes in the Rat (pgs. 239-258)

项目 3：大鼠新候选基因的功能研究（第 239-258 页）

• 批准号: 7285555
• 负责人: William E BUNNEY
• 金额: $ 26.62万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7285555
• 关键词: antidepressants; anxiety; behavioral /social science research tag; bipolar depression; brain morphology; disease /disorder etiology; emotions; fibroblast growth factor; gene expression; growth factor receptors; hippocampus; laboratory rat; major depression; microarray technology; neurogenetics; neuropathology; neuropharmacology; phenotype; psychobiology; stress; stressor

The goal of this project is to use rat models of emotional reactivity and social stress to test the function of novel candidate genes that arise from microarray studies in human postmortem brains of subjects who suffered from severe mood disorders (major depression and bipolar illness). In this proposal, we develop a specific hypothesis and describe the strategy that will be used to implicate a family of novel candidates in mood and affect. The human microarray studies (described in the Overview and in Project 1) pointed to the family of fibroblast growth factors (FGF's) and their receptors as being altered in frontal cortical regions of severely depressed patients relative to control subjects. This change in gene expression was not seen in the brain of bipolar subjects. The FGF family has been implicated in the control of development and differentiation of the brain and in neurogenesis. However, there was little evidence implicating this family in the control of emotional reactivity, stress responsiveness or mood disorders. The array findings have led us to the specific hypothesis that the FGF family is involved either in the etiology or the expression of severe depression. In order to test this hypothesis, we plan to use rats that have been screened for differential responsiveness to stress and anxiety-like situations (High Responders and Low Responders). This allows us to investigate the connection between individual differences in emotionality and anxiety-lake behavior and this gene family. In addition, these animals will either be handled (controls) or subjected to social defeat conditions (stress), which we have shown to activate the same neural pathways engaged by depression in humans. Using this animal model, we plan to address the following questions: 1) Do high responders and low responders differ in the expression of FGF-related genes, either basally or following social defeat? 2) Do various classes of antidepressants have any effects on the expression of the FGF genes, either in control or in socially defeated animals? 3) If we administer members of the FGF family to newborn rats, can we implicate them in hippocampal morphology and alterations in neurogenesis, and can we link these potential alterations to change in emotionality or stress reactivity? Together, these studies serve as a prototype for testing the potential function of genes that were not previously implicated in the severe mood disorders but whose expression is significantly altered in the brain of depressed or bipolar individuals. This will allow us to extend our understanding of the fundamental molecular and neuralmechanisms associated with mood disorders and to develop novel targets for treatment and prevention of these devastating illnesses.

该项目的目标是使用情绪反应和社会压力的大鼠模型来测试新的候选基因的功能，这些基因来自于对患有严重情绪障碍（重度抑郁症和双相情感障碍）的人死后大脑的微阵列研究。在这个建议中，我们开发了一个特定的假设，并描述了将用于牵连一个家庭的新的候选人的情绪和影响的策略。人类微阵列研究（在概述和项目1中描述）指出成纤维细胞生长因子（FGF）家族及其受体在严重抑郁症患者的额叶皮质区域相对于对照组发生了改变。这种基因表达的变化在躁郁症受试者的大脑中没有观察到。FGF家族与脑发育和分化的控制以及神经发生有关。然而，很少有证据表明这个家庭在控制情绪反应，压力反应或情绪障碍。阵列的研究结果使我们的具体假设，FGF家族参与的病因或严重抑郁症的表达。为了验证这一假设，我们计划使用已经筛选出对压力和焦虑样情况的不同反应的大鼠（高反应者和低反应者）。这使我们能够研究情绪和焦虑行为的个体差异与该基因家族之间的联系。此外，这些动物要么会被处理（控制），要么会遭受社会失败 条件（压力），我们已经证明激活了与人类抑郁症相同的神经通路。使用这种动物模型，我们计划解决以下问题：1）高反应者和低反应者在FGF相关基因的表达方面是否存在差异，无论是基础上还是在社交失败之后？2)不同种类的抗抑郁药对FGF基因的表达有影响吗？无论是在对照组还是在社会失败的动物中？3)如果我们给新生大鼠施用FGF家族的成员，我们是否可以将它们与海马形态学和神经发生的改变联系起来，我们是否可以将这些潜在的改变与情绪或应激反应的变化联系起来？总之，这些研究作为一个原型， 测试先前与严重情绪障碍无关的基因的潜在功能，但其表达在抑郁症或双相情感障碍患者的大脑中发生了显着改变。这将使我们能够扩展我们对与情绪障碍相关的基本分子和神经机制的理解，并开发治疗和预防这些毁灭性疾病的新靶点。