Validating a novel target for correction of pathophysiology in fragile X and TSC

验证用于纠正脆性 X 细胞和 TSC 病理生理学的新靶点

基本信息

批准号：
8677025
负责人：
Mark F Bear
金额：
$ 22.19万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8677025
关键词：
Adverse effects Affect Arrestins Autistic Disorder Behavior Behavioral Behavioral Assay Biochemical Biological Assay Cerebrum Clinical Trials Data Disease Fragile X Syndrome Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Gene Mutation Genetic Genetic Translation Health Hereditary Disease Hippocampus (Brain)Intellectual functioning disability Knockout Mice Left Link Measures Mediating Memory impairment Messenger RNA Methods Modeling Molecular Genetics Molecular Target Mus Mutation Neurons Other Genetics Pathway interactions Pharmacological Treatment Phenotype Phosphotransferases Process Protein Biosynthesis Recruitment Activity Regulation Risk Role Signal Pathway Signal Transduction Signaling Protein Slice Synapses Synaptic plasticity Testing Tuberous sclerosis protein complex Work arm arrestin 2 base behavioral impairment developmental disease genetic manipulation metabotropic glutamate receptor 5 mutant new therapeutic target novel protein activation protein complex receptor receptor coupling relating to nervous system research study synaptic function therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Several genetically defined developmental disorders that manifest as autism and intellectual disability, such as fragile X (FX) and tuberous sclerosis complex (TSC), have in common a disruption of activity-regulated protein synthesis at synapses. Understanding how neural activity regulates synaptic protein synthesis is crucial for identifying new therapuetic approaches for these diseases. One key mechanism employs metabotropic glutamate receptor 5 (mGluR5) but it remains to be established how this receptor couples to the mRNA translation machinery. Here we test the hypothesis that a crucial link between mGluR5 and protein synthesis is provided by ß-arrestin. Our specific aims are to characterize the effect of ss-arrestin genetic reduction on (1) mGluR5 signaling and protein synthesis in the hippocampus using biochemical methods, (2) hippocampal synaptic function and protein synthesis-dependent plasticity using electrophysiological methods, and (3) on fragile X behavioral and electrophysiological phenotypes expressed in the Fmr1 knockout mouse. If our hypothesis is correct, we expect to observe an amelioration of fragile X phenotypes by reducing ß-arrestin, validating the mGluR5-ß-arrestin protein complex as a novel therapeutic target.

描述（由适用提供）：几种表现为自闭症和智力障碍的遗传定义的发育障碍，例如脆弱的X（FX）和结节性硬化症复合物（TSC），具有共同的突触中活性调节的蛋白质合成的破坏。了解神经活动如何调节合成蛋白的合成对于确定这些疾病的新治疗方法至关重要。一种关键的机制员工代谢性谷氨酸受体5（MGLUR5），但仍有待确定该受体伴侣如何与mRNA翻译机械伴侣。在这里，我们检验了以下假设：β-arrestin提供了MGLUR5与蛋白质合成之间的关键联系。 Our specific aims are to characterize the effect of ss-arrestin genetic reduction on (1) mGluR5 signaling and protein synthesis in the hippocampus using biochemical methods, (2) hippocampal synaptic function and protein Synthesis-dependent plasticity using electrophysiological methods, and (3) on fragile X behavioral and electrophysiological phenotypes expressed in the Fmr1 knockout mouse.如果我们的假设是正确的，我们希望通过减少β-arrestin来观察脆弱的X表型的改善，从而验证MGLUR5-ß-arrestin蛋白复合物作为一种新的治疗靶标。