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

• 批准号: 8807846
• 负责人: Mark F Bear
• 金额: $ 18.25万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8807846
• 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; Methods; 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; System; Testing; Tuberous sclerosis protein complex; Work; arm; arrestin 2; audiogenic seizure; base; behavioral impairment; developmental disease; genetic manipulation; metabotropic glutamate receptor 5; mouse model; mutant; new therapeutic target; novel; protein activation; protein complex; receptor; receptor coupling; relating to nervous system; research study; synaptic function; therapeutic target

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 β-arrestin. Our specific aims are to characterize the effect of β-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 β-arrestin, validating the mGluR5-β-arrestin protein complex as a novel therapeutic target.

描述（由申请人提供）：表现为自闭症和智力残疾的几种遗传定义的发育障碍，如脆性X（FX）和结节性硬化症（TSC），共同具有突触活性调节蛋白质合成的破坏。了解神经活动如何调节突触蛋白合成对于确定这些疾病的新治疗方法至关重要。一个关键的机制采用代谢型谷氨酸受体5（mGluR 5），但它仍然是建立如何受体耦合到mRNA翻译机制。在这里，我们测试的假设，mGluR 5和蛋白质合成之间的关键环节是由β-抑制蛋白。我们的具体目标是表征β-arrestin基因减少对（1）使用生物化学方法的海马中mGluR 5信号传导和蛋白质合成的影响，（2）使用电生理学方法的海马突触功能和蛋白质合成依赖性可塑性，以及（3）对Fmr 1敲除小鼠中表达的脆性X行为和电生理表型的影响。如果我们的假设是正确的，我们期望通过减少β-arrestin来观察脆性X表型的改善，从而验证mGluR 5-β-arrestin蛋白复合物作为新的治疗靶点。