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: 6850575
• 负责人: William E BUNNEY
• 金额: $ 28.81万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850575
• 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.

该项目的目标是利用情绪反应和社会压力的大鼠模型来测试新候选基因的功能，这些候选基因是通过对患有严重情绪障碍（重度抑郁症和双相情感障碍）的人类死后大脑进行微阵列研究而产生的。在这个提案中，我们提出了一个具体的假设，并描述了将用于在情绪和情感上暗示一系列新候选人的策略。人类微阵列研究（在概述和项目 1 中进行了描述）指出，相对于对照受试者，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皮质区域发生了改变。在双相情感障碍受试者的大脑中没有发现这种基因表达的变化。 FGF 家族参与大脑发育和分化的控制以及神经发生。然而，几乎没有证据表明这个家庭能够控制情绪反应、压力反应或情绪障碍。阵列结果使我们得出一个具体假设：FGF 家族参与严重抑郁症的病因或表达。为了检验这一假设，我们计划使用经过筛选的老鼠，这些老鼠对压力和类似焦虑的情况有不同的反应（高反应者和低反应者）。这使我们能够研究情绪和焦虑湖行为的个体差异与该基因家族之间的联系。此外，这些动物要么被处理（控制），要么遭受社会失败 我们已经证明，压力可以激活与人类抑郁症相同的神经通路。使用该动物模型，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，无论是基础性的还是社交失败后的差异？ 2) 各类抗抑郁药对对照动物或在社会上失败的动物中的 FGF 基因表达有影响吗？ 3) 如果我们将 FGF 家族的成员给予新生大鼠，我们是否可以将它们与海马形态和神经发生的改变联系起来，并且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？这些研究共同构成了以下研究的原型： 测试以前与严重情绪障碍无关但其表达在抑郁或躁郁症个体大脑中显着改变的基因的潜在功能。这将使我们能够扩展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。