The Mechanisms of Homer1a Transcription and Dynamics with Persistent mTOR in Alzheimer's Disease

项目摘要 大约十分之一的65岁以上的人患有阿尔茨海默病（AD），这是一种毁灭性的疾病， 无法预防治愈甚至无法减缓因此，迫切需要确定新的治疗方法， 阿尔茨海默病的靶点和生物标志物。越来越多的证据表明，在AD中， 由于错误的突触可塑性（学习的分子驱动力）， 记忆Homer1a是一种响应神经元活动而表达的蛋白质，其对于各种形式的神经元活动是必需的。 突触可塑性此外，Homer1a表达在小鼠AD模型以及AD患者中被破坏。 样品尽管有这些信息，活动诱导Homer1a表达背后的机制，以及如何 这在AD中被破坏，仍然不清楚。我们最近对持续性mTOR的小鼠模型进行了表征 信号传导，这是AD中经常报告的特征，并且生成的数据显示Homer1a诱导蛋白在AD中丢失。 该模型拟议的研究项目结合了分子生物学，基因表达技术， 各种体内和体外神经元活动模型，以阐明Homer1a表达的机制 并确定这些机制在持续性mTOR信号传导和AD中是如何被破坏的。完成 对这种对可塑性至关重要且在AD中失调的基因的拟议研究将阐明其调控机制。 生理和病理机制，这可能导致新的治疗策略， 阿尔茨海默病的潜在生物标志物。

PROJECT SUMMARY Approximately 1 in 10 people over the age of 65 have Alzheimer's disease (AD), a devastating illness that cannot be prevented, cured, or even slowed. Hence there is an urgent need to identify novel therapeutic targets and biomarkers for Alzheimer's Disease. Accumulating evidence suggests that in AD the brain is unable to process information properly due to faulty synaptic plasticity, the molecular driver of learning and memory. Homer1a is a protein expressed in response to neuronal activity that is essential for various forms of synaptic plasticity. Further, Homer1a expression is disrupted in mouse AD models as well as AD patient samples. Despite this information, the mechanism behind activity-induced Homer1a expression, as well as how this is disrupted in AD, remains unclear. We recently characterized a mouse model of persistent mTOR signaling, a characteristic often reported in AD, and generated data showing that Homer1a inducibility is lost in this model. The proposed research project combines molecular biology, gene expression techniques, and various in vivo and in vitro models of neuronal activity to elucidate the mechanisms of Homer1a expression and determine how these mechanisms are disrupted in persistent mTOR signaling and AD. Completion of the proposed study on this gene essential for plasticity and dysregulated in AD will shed light on its regulatory mechanisms, both physiologically and pathologically, which may lead to new therapeutic strategies and potential biomarkers for Alzheimer's Disease.