通过 AKAP 锚定的钙调神经磷酸酶进行淀粉样蛋白突触后信号传导-猫眼课题宝

通过 AKAP 锚定的钙调神经磷酸酶进行淀粉样蛋白突触后信号传导

批准号：

9180008

负责人：

MARK L DELL'ACQUA

金额：

$23.33万

依托单位：

UNIVERSITY OF COLORADO DENVER

依托单位国家：

美国

项目类别：

财政年份：

2016

资助国家：

美国

项目状态：

已结题

起止时间：

2016-07-01 至 2018-06-30

来源：

https://reporter.nih.gov/project-details/9180008

关键词：

A kinase anchoring protein Adult Age Aging Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Brain Calcineurin Calcineurin inhibitor Calmodulin Cell Nucleus Chromosomes, Human, Pair 21 Chronic Conflict (Psychology)Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Dementia Dendritic Spines Development Diagnostic Docking Down Syndrome Drug Targeting Equilibrium Excision Excitatory Synapse Functional disorder Future Gene Expression General Population Genes Genetic Transcription Genetically Engineered Mouse Glutamate Receptor Hippocampus (Brain)Human Human Chromosomes Impaired cognition Individual Inherited Intellectual functioning disability Knock-in Mouse Laboratories Learning Light Link Long-Term Depression Long-Term Potentiation Mediating Memory Memory impairment Molecular Mus N-Methylaspartate Nerve Degeneration Neuronal Dysfunction Neuronal Plasticity Neurons Nuclear Translocation PPP3CA gene Pathology Pathway interactions Phenotype Phosphorylation Phosphotransferases Presenile Alzheimer Dementia Protein Dephosphorylation Protein Fragment Proteins Publishing Receptor Activation Regulation Reporting Research Rodent Rodent Model Role Scaffolding Protein Signal Pathway Signal Transduction Synapses Synaptic plasticity T cell regulation Testing Vertebral column abstracting calcineurin phosphatase cognitive function early onset innovation interest mouse model new therapeutic target novel novel diagnostics nuclear factors of activated T-cells overexpression postsynaptic prevent receptor response synaptic depression synaptic function targeted treatment tau Proteins transcription factor voltage

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中文摘要

翻译

项目摘要 AKAP锚定的钙调神经磷酸酶介导的β淀粉样蛋白突触后信号转导据信，APP的过度产生导致突触可塑性受损，并降低了突触可塑性。阿尔茨海默病（AD）的认知功能。患有唐氏综合征（DS; 21三体）的个体有额外的 APP的拷贝，使他们易患早发性AD。因此，阐明A β如何抑制可塑性是重要的了解与AD和DS痴呆发展相关的认知障碍，确定新的药物靶点、诊断和治疗。啮齿动物模型研究表明，钙调神经磷酸酶（CaN）磷酸酶信号传导可能有助于改变LTP/LTD突触可塑性，树突棘丢失，学习和记忆障碍。脊髓损伤引起的脊髓缺失可能与基因改变有关。通过CaN激活转录因子NFAT表达。在这里，我们建议测试小说假设AKAP 79/150-CaN锚定是调节细胞凋亡的CaN信号转导的A β激活所必需的， LTP/LTD信号传导和NFAT转录之间的平衡与树突棘/突触丢失相关。

英文摘要

Project Summary Abstract Amyloid Beta Postsynaptic Signaling through AKAP-anchored Calcineurin A overproduction from APP is believed to contribute to impaired synaptic plasticity and decreased cognitive function in Alzheimer’s disease (AD). Individuals with Down syndrome (DS; trisomy 21) have an extra copy of APP that predisposes them to early-onset AD. Thus, elucidating how A inhibits plasticity is important for understanding cognitive impairments associated with the development of dementia in AD and DS and could identify novel drug targets, diagnostics, and therapies. Rodent model studies indicate that calcineurin (CaN) phosphatase signaling could contribute to altered LTP/LTD synaptic plasticity, dendritic spine loss, and learning and memory impairments in AD. A-induced spine loss may be further linked to altered gene expression through CaN activation of the transcription factor NFAT. Here we propose to test the novel hypotheses that AKAP79/150-CaN anchoring is required for A activation of CaN signaling that regulates the balance between LTP/LTD signaling and NFAT transcription associated with dendritic spine/synapse loss.

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