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

• 批准号: 8586905
• 负责人: Hongbing Wang
• 金额: $ 37.79万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586905
• 关键词: Address; Animal Model; Attenuated; Autistic Disorder; Behavior; Behavioral; Cognition; Coupled; Cyclic AMP; Data; Enzymes; Etiology; Fragile X Mental Retardation Protein; Fragile X Syndrome; Functional disorder; Gene Mutation; Genes; Genetic; 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; innovation; insight; mouse model; novel; novel therapeutics; preclinical study; relating to nervous system; social; synaptic function; therapeutic development; therapeutic target; treatment strategy

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（申请人提供）：脆性X综合征（FXS）是一种常见的精神障碍，由Fmr1基因突变导致FMRP（脆性X智力低下蛋白）表达缺失引起。使用动物模型进行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 相关的表型的许多方面，包括认知缺陷、多动、过度兴奋和社交能力受损。与 FXS 相关的一个主要病理生理学是增强的 I 类代谢型谷氨酸受体 (mGluR) 介导的突触长期抑制 (mGluR-LTD)，表明 mGluR 信号传导的过度激活可能在 FXS 病因学中发挥作用。因此，非常需要鉴定 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，尚不清楚 cAMP 是否是 mGluR 信号级联中的功能成分。确定控制 FXS 中基础 cAMP 水平并实现治疗的具体方法也很重要。 与 NIH 的使命一致，该提案旨在鉴定 mGluR 信号级联中的新成分，并验证在小鼠动物模型中治疗 FXS 的新治疗策略。该提案的目标是 1) 确定 mGluR 和 cAMP 如何偶联，2) 确定如何操纵 FXS 小鼠模型中的基础以及 mGluR 刺激的 cAMP 水平，以及 3) 确定 FXS 中 cAMP 操纵的治疗价值。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 病理学背后的关键分子和细胞机制来进一步检查其治疗价值。我们期望这项工作将确定新的机制并提出治疗 FXS 的新策略。我们操纵 cAMP 的方法及其在 FXS 中的治疗价值将在使用 FXS 动物模型的临床前研究中得到验证。由于 Fmr1 基因突变也是导致自闭症的主要原因，因此有人认为 FXS 和自闭症可能有一些共同的机制。因此，我们预计该提案的结果也可能有助于理解自闭症所涉及的信号转导。