Equipment Supplement to 'Development of promoters of dendritic spine formation'

项目摘要 阿尔茨海默病等神经退行性疾病患者的公共健康影响 疾病(AD)正在以惊人的速度增长，无论是在美国还是在全球。对经济形势的预测 负担和生产率损失差异很大，但所有估计都高得令人不安。例如，人们认为， 全球被诊断为阿尔茨海默病的患者数量将从目前的2,000-2,500万上升到 假设没有出现有效的治疗策略，到2050年，这一数字将是这个数字的三倍。当前的方法是 试图抑制阿尔茨海默病认知功能下降，如抗淀粉样蛋白免疫治疗，目前仅有表现 在最近的临床试验中效果不大。因此，迫切需要探索小说。 干预或逆转与阿尔茨海默病和相关疾病相关的神经病理效应的方法。 阿尔茨海默病患者最明显的临床症状之一是显著的记忆力丧失 以及无法回忆起新学到的信息。我们假设一种可以提高记忆力的方法 因此，学习可能是一种有效的策略，可以逆转这种影响或减缓其进展。 神经退行性疾病，如阿尔茨海默病。为了探索这样一种新颖的战略，我们最近 开发了一种具有类药物性质的合成分子(BTA-EG4)，该分子具有改善 野生型小鼠和阿尔茨海默病模型小鼠的记忆和学习，还发现促进树突状细胞 神经元中的棘突形成(体内和体外)。因为树突棘密度与记忆密切相关 在人类发育和学习方面，我们假设改善了小鼠的记忆和学习能力 与BTA-EG4有关的是促进脊椎发生的分子能力。为了跟进这件事 这些初步发现，本研究试图对BTA-EG4和BTA-EG4的活性有更广泛的了解 相关化合物。我们将寻求更好地描述受BTA-EG4影响的细胞机制。 令人兴奋的初步数据显示，我们已经初步确定了BTA-EG4的细胞靶点 光亲和下拉实验。该提案旨在1)验证BTA-EG4的细胞靶点，从而导致 增加树突棘密度，2)开发BTA类似物家族，以更好地表征它们的能力 促进树突棘和优化刺生活性，以及3)探索BTA类似物是否可以促进 人类神经元中树突棘的密度。 本研究的总体目标将是阐明其作用的分子机制。 导致树突棘密度增加的BTA化合物。这项研究的直接结果将是 发现了一种新的药物开发途径，可以改善认知能力 将是管理人类心理健康的一项重要资源，但目前尚不具备。

Project Summary The public health impact of patients suffering from neurodegenerative disorders such as Alzheimer disease (AD) is increasing at an alarming rate, both in the US and globally. Projections of the economic burden and lost productivity vary widely, but all estimates are disturbingly high. It is believed, for instance, that the number of patients diagnosed with AD will rise from the current value of 20-25 million worldwide to up to three times that number by 2050, assuming no effective treatment strategy emerges. Current approaches to try to curb the decline of cognitive function in AD, such as anti-amyloid immunotherapy, are showing only modest effect in the most recent clinical trials. Therefore, there is an immediate need to explore novel approaches to intervene or reverse the neuropathic effects associated with AD and related diseases. Among the most overt clinical symptoms of patients suffering from AD is the significant loss of memory and the inability to recall newly learned information. We hypothesize that a method that can improve memory and learning may, therefore, be an effective strategy to reverse the effects or slow down the progression of neurodegenerative diseases such as AD. In an effort to explore such a novel strategy, we have recently developed a synthetic molecule with drug-like properties (BTA-EG4) that exhibits the capability of improving memory and learning in wild type mice and in an AD mouse model and was also found to promote dendritic spine formation in neurons (in vivo and in vitro). Since dendritic spine density correlates strongly with memory and learning in human development, we hypothesize that the improved memory and learning in mice treated with BTA-EG4 is related to the capability of the molecule to promote spinogenesis. In order to follow up on these initial findings, this research seeks to gain a broader understanding of the activity of BTA-EG4 and related compounds. We will seek to better characterize the cellular machinery that is affected by BTA-EG4. Exciting preliminary data shows that we have tentatively identified the cellular target for BTA-EG4 through photoaffinity pulldown assays. This proposal seeks to 1) validate the cellular target of BTA-EG4 that leads to increase in dendritic spine density, 2) develop a family of BTA analogs to better characterize their capability to promote dendritic spines and to optimize spinogenic activity, and 3) explore whether BTA analogs can promote dendritic spine density in human neurons. The overall goal of this research will be the elucidation of the molecular mechanism of action of the BTA compounds that leads to an increase in dendritic spine density. A direct outcome of this research will be the identification of a new avenue for drug development leading to improved cognitive performance, which would represent an important and currently unavailable resource for the management of human mental health.