5-HT2C-receptor expression and function in depression
抑郁症中 5-HT2C 受体的表达和功能
基本信息
- 批准号:6325053
- 负责人:
- 金额:$ 29.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-04-01 至 2004-03-31
- 项目状态:已结题
- 来源:
- 关键词:3T3 cells G protein RNA splicing antidepressants human tissue laboratory mouse major depression male nucleic acid sequence pharmacokinetics polymerase chain reaction postmortem posttranscriptional RNA processing prefrontal lobe /cortex protein isoforms protein structure function receptor binding receptor coupling receptor expression serotonin receptor statistics /biometry suicide
项目摘要
DESCRIPTION: (Applicant's abstract) The expression and function of one subtype
of serotonin (5-HT) receptors, the 5-HT2C receptor, is regulated by RNA editing
and alternative splicing of its encoded pre-mRNA. In postmortem prefrontal
cortical tissue from depressed suicide victims, the editing pattern of 5-HT2C
pre-mRNA differs significantly from the editing pattern of control brains that
could potentially result in a decreased efficiency of 5-HT2C receptor-G protein
interactions. The overall objectives of the proposed research plan are to
varify further a possible relationship between depression and an altered
editing pattern of prefrontal cortical 5-HT2C pre-mRNA, and to define the
possible functional consequences of this altered editing pattern and to test
possible underlying mechanisms. Three specific aims are proposed to attain
these objectives. In specific aim 1, the investigator proposes an extended
replication of the differential 5-HT2C editing finding piloting this work. The
5-HT2C receptor editing pattern would be compared in brains of groups of male
depressed suicide victims and depressed non-suicide subjects to assess the
relative contribution of depression versus suicide. Editing patterns of 5-HT2C
receptor mRNAs would be identified by nucleotide sequencing of cDNAs generated
by RT-PCR. Proposed specific aim 2 would assess the functional significance of
altered 5 HT2C receptor mRNA editing using stably transfected lines of NIH3T3
cells that express the three major altered 5-HT2C receptor isoforms associated
with depression, as well as the more rare nonedited and fully edited isoforms.
Functional assays would determine the comparative ability of the edited and
nonedited isoforms to couple to G protein and activate the phospholipase C
second messenger system. The effects of RNA editing on the guanyl nucleotide
sensitivity of 5-HT2C receptor-G protein interactions, and the interaction of
different receptor isoforms would also be preliminarily assessed. Related
functional experiments would compare GTP(S binding to membranes of prefrontal
cortical tissues of depressed suicide victims and depressed non-suicide
subjects to determine the effect of 5-HT2C editing alterations associated with
depression on basal and agonist-promoted activation of G proteins by 5-HT2C
receptors. Specific aim 3 would compare the effects of mechanistically distinct
antidepressants, and the 5-HT2A/2C receptor antagonist ketanserin, on the
neocortical 5-HT2C receptor RNA editing pattern, in wild-type mice. These
studies would attempt to assess whether the observed alteration of 5-HT2C RNA
editing in depression reflects medication effects.
描述:(申请人摘要)一种亚型的表达和功能
5-羟色胺(5-HT)受体,即5-HT 2C受体,受RNA编辑调控
以及其编码的前mRNA的选择性剪接。在死后前额叶
抑郁自杀受害者的皮层组织,5-HT 2C的编辑模式
前mRNA与对照组大脑的编辑模式显著不同,
可能导致5-HT 2C受体-G蛋白的效率降低
交互.拟议研究计划的总体目标是
进一步证实了抑郁症和改变的
前额叶皮质5-HT 2C前体mRNA的编辑模式,并定义
这种改变的编辑模式的可能功能后果,并测试
可能的潜在机制。建议实现三个具体目标
这些目标。在具体目标1中,研究人员提出了一个扩展的
复制差异5-HT 2C编辑发现引导这项工作。的
5-HT 2C受体编辑模式将在男性组的脑中进行比较。
抑郁的自杀受害者和抑郁的非自杀受试者,以评估
抑郁症与自杀的相对贡献。5-HT 2C的编辑模式
通过对产生的cDNA进行核苷酸测序来鉴定受体mRNA,
用RT-PCR拟议的具体目标2将评估以下方面的职能意义:
使用稳定转染的NIH 3 T3细胞系改变5-HT 2C受体mRNA编辑
表达三种主要改变的5-HT 2C受体亚型的细胞,
抑郁症,以及更罕见的未经编辑和完全编辑的亚型。
功能测定将确定编辑的和未编辑的蛋白质的比较能力。
未编辑的同种型与G蛋白偶联并激活磷脂酶C
第二信使系统RNA编辑对鸟苷酸的影响
5-HT 2C受体-G蛋白相互作用的敏感性,以及
还将初步评估不同的受体同种型。相关
功能实验将比较GTP(S)与前额叶膜的结合,
抑郁的自杀受害者和抑郁的非自杀受害者的皮层组织
受试者,以确定5-HT 2C编辑改变与
5-HT 2C抑制G蛋白的基础和激动剂促进的激活
受体。具体目标3将比较机械上不同的
抗抑郁药和5-HT 2A/2C受体拮抗剂酮色林,
新皮质5-HT 2C受体RNA编辑模式,在野生型小鼠中。这些
研究将试图评估观察到的5-HT 2C RNA的改变是否
抑郁症的编辑反映了药物作用。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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CLAUDIA SCHMAUSS其他文献
CLAUDIA SCHMAUSS的其他文献
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{{ truncateString('CLAUDIA SCHMAUSS', 18)}}的其他基金
Epigenetic modulation of antidepressant efficacy
抗抑郁功效的表观遗传调节
- 批准号:
8706970 - 财政年份:2013
- 资助金额:
$ 29.84万 - 项目类别:
Epigenetic modulation of antidepressant efficacy
抗抑郁功效的表观遗传调节
- 批准号:
8582998 - 财政年份:2013
- 资助金额:
$ 29.84万 - 项目类别:
Genetic and environmental modulation of RNA editing
RNA编辑的遗传和环境调节
- 批准号:
7743836 - 财政年份:2008
- 资助金额:
$ 29.84万 - 项目类别:
Genetic and environmental modulation of RNA editing
RNA编辑的遗传和环境调节
- 批准号:
7991781 - 财政年份:2008
- 资助金额:
$ 29.84万 - 项目类别:
Genetic and environmental modulation of RNA editing
RNA编辑的遗传和环境调节
- 批准号:
7563296 - 财政年份:2008
- 资助金额:
$ 29.84万 - 项目类别:
5-HT2C-receptor expression and function in depression
抑郁症中 5-HT2C 受体的表达和功能
- 批准号:
6539139 - 财政年份:2001
- 资助金额:
$ 29.84万 - 项目类别:
5-HT2C-receptor expression and function in depression
抑郁症中 5-HT2C 受体的表达和功能
- 批准号:
6639197 - 财政年份:2001
- 资助金额:
$ 29.84万 - 项目类别:
5-HT2C receptor expression and function in depression
抑郁症中5-HT2C受体的表达和功能
- 批准号:
7120761 - 财政年份:2000
- 资助金额:
$ 29.84万 - 项目类别:
D3 pre-mRNA processing in chronic psychosis
慢性精神病中的 D3 mRNA 前体加工
- 批准号:
6832176 - 财政年份:1997
- 资助金额:
$ 29.84万 - 项目类别:
D3 PREMRNA PROCESSING IN CHRONIC PSYCHOSIS
慢性精神病中的 D3 前体 RNA 加工
- 批准号:
2864068 - 财政年份:1997
- 资助金额:
$ 29.84万 - 项目类别:
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