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

项目总结 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，迫切需要找到新的治疗方法 阿尔茨海默病的靶点和生物标记物。越来越多的证据表明，在AD中，大脑 由于突触可塑性缺陷，学习和学习的分子驱动因素无法正确处理信息 记忆。Hmer 1a是一种响应神经元活动而表达的蛋白质，对于各种形式的 突触可塑性。此外，在小鼠AD模型和AD患者中，Hmer 1a的表达被破坏 样本。尽管有这些信息，但活动诱导Hmer 1a表达背后的机制以及如何 这在公元后被打乱了，目前仍不清楚。我们最近描述了一种持续性mTOR的小鼠模型 信号，这是AD中经常报告的一个特征，生成的数据显示，Hmer 1a的诱导性在 这个型号。拟议的研究项目结合了分子生物学、基因表达技术和 不同的体内和体外神经元活性模型来阐明Hmer 1a表达的机制 并确定这些机制在持久性mTOR信令和AD中是如何被破坏的。已完成的 对该基因在AD中的可塑性和失调的研究将有助于揭示其调控机制 生理和病理机制，这可能导致新的治疗策略和 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.