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Genetic and environmental modulation of RNA editing

RNA编辑的遗传和环境调节

基本信息

批准号：
7991781
负责人：
CLAUDIA SCHMAUSS
金额：
$ 28.62万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-04 至 2012-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Early life stress is a prominent risk factor for adult-onset depressive illness. In both humans and rodents, early life stress leads to changes in several physiological measures that persist into adulthood. In a genetically distinct inbred strain of mice with lower forebrain serotonin, spontaneously elevated anxiety, and increased stress reactivity (Balb/c), early life stress leads to several changes in neuronal gene expression in adulthood. These changes include increased expression of serotonin 2C (5-HT2C) receptor mRNA isoforms that result from RNA editing and encode receptors with reduced function. Such changes in 5-HT2C receptor editing have also been found in brains of depressed suicide victims. Studies on Balb/c mice showed that changes in 5-HT2C receptor editing are accompanied by altered expression of the alpha subunit of Gq protein that couples to this receptor. They further showed that treatment with the antidepressant drug fluoxetine during adolescence significantly decreased the abnormally increased 5-HT2C pre-mRNA editing that resulted from early life stress and also reversed corresponding alterations in G alpha q protein expression. Similar to the effect of adolescent fluoxetine in mice exposed to early life stress, postweaning environmental enrichment diminished the magnitude of hightened behavioral responses to adult stress. However, in contrast to fluoxetine, postweaning enrichment did not alter the abnormal 5-HT2C pre-mRNA editing phenotype. In this proposal, a cross-fostering paradigm between Balb/c and stress-resistant C57Bl/6 mice is used to test the impact of genetic factors, environmental factors, and adolescent antidepressant treatment on the modulation of 5-HT2C receptor editing phenotypes. It further tests potential mechanisms leading to increased 5-HT2C pre-mRNA editing in Balb/c mice exposed to early life stress. One hypothesis is that early life stress alters the expression of distinct isoforms of the editing enzymes ADAR1/2 via alternative splicing to yield mRNA encoding enzymes with higher catalytic activities. Another hypothesis, tested with studies on transfected cells, is that G alpha q protein is a critical mediator of the serotonin-dependent regulation of 5-HT2C pre-mRNA editing. Finally, molecular and anatomic studies will demonstrate that changes in 5-HT2C pre-mRNA editing that result from early life stress are also accompanied by changes in the expression of other genes that are either potential mediators of epigenetic changes in gene expression, transcriptional or post-transcriptional modulators of gene expression, or involved in synaptic functions, and that many of these changes in gene expression are functionally linked to depression and differentially modulated by genetic factors, environmental influences, and antidepressant treatment.

描述（由申请人提供）：早期生活压力是成年发病抑郁症的一个重要危险因素。对于人类和啮齿动物来说，早期生活压力会导致一些生理指标的变化，这种变化会持续到成年期。在具有较低前脑血清素、自发性焦虑升高和应激反应性增加（Balb/c）的遗传上独特的近交系小鼠中，早期生活压力导致成年期神经元基因表达的一些变化。这些变化包括 RNA 编辑导致的血清素 2C (5-HT2C) 受体 mRNA 亚型表达增加，以及编码功能减弱的受体。在抑郁症自杀者的大脑中也发现了 5-HT2C 受体编辑的这种变化。对 Balb/c 小鼠的研究表明，5-HT2C 受体编辑的变化伴随着与该受体偶联的 Gq 蛋白 α 亚基表达的改变。他们进一步表明，在青春期使用抗抑郁药物氟西汀治疗可显着减少因早期生活压力导致的异常增加的 5-HT2C 前体 mRNA 编辑，并逆转 G α q 蛋白表达的相应变化。与青春期氟西汀对暴露于早期生活压力的小鼠的作用类似，断奶后环境丰富化降低了对成年压力的行为反应的强度。然而，与氟西汀相反，断奶后富集并没有改变异常的 5-HT2C 前 mRNA 编辑表型。在该提案中，使用 Balb/c 和抗应激 C57Bl/6 小鼠之间的交叉培养范例来测试遗传因素、环境因素和青少年抗抑郁治疗对 5-HT2C 受体编辑表型调节的影响。它进一步测试了导致暴露于早期生活压力的 Balb/c 小鼠中 5-HT2C 前 mRNA 编辑增加的潜在机制。一种假设是，早期生活压力通过选择性剪接改变了编辑酶 ADAR1/2 的不同亚型的表达，从而产生具有更高催化活性的编码酶的 mRNA。通过对转染细胞的研究测试的另一个假设是，G α q 蛋白是 5-HT2C 前 mRNA 编辑的血清素依赖性调节的关键介质。最后，分子和解剖学研究将证明，由早期生活压力引起的 5-HT2C mRNA 前体编辑的变化也伴随着其他基因表达的变化，这些基因要么是基因表达表观遗传变化的潜在介质，基因表达的转录或转录后调节剂，要么参与突触功能，并且许多基因表达的变化在功能上与抑郁症相关，并受到遗传因素的差异调节。因素、环境影响和抗抑郁治疗。