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卫生影响 在美国和全球范围内，阿尔茨海默病（AD）正以惊人的速度增长。经济预测 负担和生产力损失差异很大，但所有估计都高得令人不安。例如，人们认为， 全球诊断为AD的患者数量将从目前的2000 - 2500万增加到 到2050年，如果没有有效的治疗策略，这个数字将增加三倍。的当前方法 试图抑制AD认知功能下降的药物，如抗淀粉样蛋白免疫疗法， 在最新的临床试验中效果一般。因此，迫切需要探索小说 干预或逆转与AD和相关疾病相关的神经病变效应的方法。 在患有AD的患者的最明显的临床症状中是记忆的显著丧失 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，可以扭转这种影响或减缓这种进展。 神经退行性疾病如AD。为了探索这种新颖的策略，我们最近 开发了一种具有药物样特性的合成分子（BTA-EG 4），该分子具有改善 在野生型小鼠和AD小鼠模型中， 神经元中的棘形成（体内和体外）。由于树突棘密度与记忆力密切相关 和学习能力，我们假设，小鼠的记忆力和学习能力的改善， 与BTA-EG 4的结合与该分子促进棘发生的能力有关。为落实 这些初步的发现，这项研究旨在获得更广泛的了解BTA-EG 4的活动， 相关化合物。我们将寻求更好地表征受BTA-EG 4影响的细胞机制。 令人兴奋的初步数据表明，我们已经初步确定了BTA-EG 4的细胞靶点， 光亲和下拉测定。该提议寻求1）验证BTA-EG 4的细胞靶点，其导致 树突棘密度增加，2）开发了一个BTA类似物家族，以更好地表征其 促进树突棘并优化棘原活性，以及3）探索BTA类似物是否可以促进 树突棘密度。 本研究的总体目标将是阐明的分子机制的行动， 导致树突棘密度增加的BTA化合物。这项研究的一个直接成果将是 确定一种新的药物开发途径，从而改善认知能力， 将是一个重要的和目前不可用的资源，用于人类心理健康的管理。

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.