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Connecting mGluR and cAMP in the pre-clinical model of Fragile X

在 Fragile X 的临床前模型中连接 mGluR 和 cAMP

基本信息

批准号：
8973575
负责人：
Hongbing Wang
金额：
$ 37.75万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8973575
关键词：
Address Animal Model Attenuated Autistic Disorder Behavior Behavioral Cognition Coupled Cyclic AMP DNA Sequence Alteration Data Enzymes Etiology FMR1 Fragile X Syndrome Functional disorder Genes Goals Hyperactive behavior Knockout Mice Link Long-Term Depression Measures Mediating Mental Retardation Mental disorders Metabotropic Glutamate Receptors Methods Mission Molecular Mus Mutation Neuraxis Neurons Normal Range Outcome Pathology Peripheral Phenotype Play Pre-Clinical Model Production Proteins Receptor Signaling Research Role Signal Pathway Signal Transduction Synapses Therapeutic Therapeutic Effect Tissues Translations United States National Institutes of Health Vertebral column Work adenylyl cyclase 1 base density fighting genetic approach innovation insight mouse model novel novel therapeutic intervention preclinical study relating to nervous system repetitive behavior social synaptic function therapeutic development therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is a common form of mental disorder caused by genetic mutation in Fmr1 gene that leads to lack of expression of FMRP (fragile X mental retardation protein). Tremendous advances in understanding FXS are made from pre-clinical studies using animal models. The Fmr1 knockout mouse model replicates many aspects of phenotypes associated with FXS, including cognition deficits, hyperactivity, hyperarousal, and impaired social ability. One major pathophysiology associated with FXS, the enhanced group I metabotropic glutamate receptor (mGluR)-mediated synaptic long-term depression (mGluR-LTD), implicates that overactivation of mGluR signaling may play a role in FXS etiology. Thus, there is significant need to identify key molecular components in the mGluR signaling cascade and develop therapeutic strategies. Here, we found that lowering basal cAMP level caused an opposite synaptic phenotype to that of FXS. However, it is not known whether cAMP is a functional component in the mGluR signaling cascade. It is also important to identify specific approaches to manipulate basal cAMP level in FXS and achieve therapy. Consistent with the mission of NIH, this proposal aims to identify a novel component in the mGluR signaling cascade and validate a new therapeutic strategy for the treatment of FXS in mouse animal model. The goals of this proposal are 1) to determine how mGluR and cAMP are coupled, 2) to determine how to manipulate the basal, as well as mGluR-stimulated cAMP level in the mouse model of FXS, and 3) to determine the therapeutic value of cAMP manipulation in FXS. We will use genetic approaches to manipulate the cAMP level. We will further examine the therapeutic value by measuring mGluR-LTD, the core FXS-associated behavioral phenotypes, and the key molecular and cellular mechanisms underlying the pathology of FXS. We expect that this work will identify novel mechanism and suggest new strategy to treat FXS. Our method of manipulating cAMP and its therapeutic value in FXS will be validated in pre-clinical studies using an FXS animal model. Because mutation of Fmr1 gene is also a leading cause for autism, it has been suggested that FXS and autism may share some common mechanisms. Thus, we expect that the outcome of this proposal may also help understanding the signal transduction involved in autism.

描述（由申请人提供）：脆性X综合征（Fragile X syndrome， FXS）是一种常见的精神障碍，由Fmr1基因突变导致FMRP（脆性X智力迟钝蛋白）缺乏表达引起。使用动物模型的临床前研究在理解FXS方面取得了巨大进展。Fmr1敲除小鼠模型复制了与FXS相关的许多表型，包括认知缺陷、多动、过度觉醒和社交能力受损。与FXS相关的一个主要病理生理机制是I组代谢型谷氨酸受体（mGluR）介导的突触长期抑制（mGluR- ltd）的增强，这表明mGluR信号的过度激活可能在FXS的病因中发挥作用。因此，有必要确定mGluR信号级联中的关键分子成分并制定治疗策略。在这里，我们发现降低基础cAMP水平会导致与FXS相反的突触表型。然而，目前尚不清楚cAMP是否是mGluR信号级联中的一个功能成分。确定特定的方法来控制FXS的基础cAMP水平并实现治疗也很重要。与NIH的使命一致，本提案旨在确定mGluR信号级联中的新组分，并在小鼠动物模型中验证治疗FXS的新治疗策略。本课题的目标是：1)确定mGluR和cAMP是如何偶联的；2)确定如何操纵FXS小鼠模型中mGluR刺激的基础cAMP水平；3)确定cAMP操纵在FXS中的治疗价值。我们将使用遗传方法来操纵cAMP水平。我们将通过测量mGluR-LTD、FXS相关的核心行为表型以及FXS病理背后的关键分子和细胞机制来进一步检验其治疗价值。我们希望这项工作能够发现新的机制，并提出新的治疗FXS的策略。我们操纵cAMP的方法及其在FXS中的治疗价值将在FXS动物模型的临床前研究中得到验证。由于Fmr1基因突变也是自闭症的主要原因，因此有人认为FXS和自闭症可能有一些共同的机制。因此，我们期望这一建议的结果也可能有助于理解自闭症的信号转导。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acute inhibition of mGluR5 disrupts behavioral flexibility.

mGluR5 的急性抑制会破坏行为灵活性。

DOI：
10.1016/j.nlm.2016.01.004
发表时间：
2016
期刊：
Neurobiology of learning and memory
影响因子：
2.7
作者：
Sethna,Ferzin;Wang,Hongbing
通讯作者：
Wang,Hongbing

A reduced susceptibility to chemoconvulsant stimulation in adenylyl cyclase 8 knockout mice.

DOI：
10.1016/j.eplepsyres.2015.11.007
发表时间：
2016-01
期刊：
Epilepsy research
影响因子：
2.2
作者：
Chen X;Dong G;Zheng C;Wang H;Yun W;Zhou X
通讯作者：
Zhou X

Behavioral analysis of male and female Fmr1 knockout mice on C57BL/6 background.

在C57BL/6背景上对男性和女性FMR1敲除小鼠的行为分析。

DOI：
10.1016/j.bbr.2014.05.046
发表时间：
2014-09-01
期刊：
BEHAVIOURAL BRAIN RESEARCH
影响因子：
2.7
作者：
Ding, Qi;Sethna, Ferzin;Wang, Hongbing
通讯作者：
Wang, Hongbing

Involvement of BDNF/ERK signaling in spontaneous recovery from trimethyltin-induced hippocampal neurotoxicity in mice.

DOI：
10.1016/j.brainresbull.2016.01.002
发表时间：
2016-03
期刊：
Brain research bulletin
影响因子：
3.8
作者：
Lee S;Yang M;Kim J;Son Y;Kim J;Kang S;Ahn W;Kim SH;Kim JC;Shin T;Wang H;Moon C
通讯作者：
Moon C

Pharmacological enhancement of mGluR5 facilitates contextual fear memory extinction.