Novel Protein Aggregation Inhibitors and Upper Motor Neuron Stabilizers for ALS and other Neurodegenerative Diseases

摘要： 化学、遗传学和生物学的最新发展表明，许多与年龄相关的神经退行性疾病， 肌萎缩性侧索硬化症（ALS）、阿尔茨海默病和ALS/FTD等疾病共享蛋白质 积累作为神经病理学的常见原因。此外，化合物的数量和种类 在过去的几年里，它呈指数级增长。然而，这些科学发展并没有 但却成功地转化为对患者有效的药物发现。这是一个合作项目。 Silverman和Ozdinler实验室之间的合作，融合了药物化学和选择性神经元 脆弱性，分别。为了加快药物发现和鉴定新的化合物， ALS和年龄相关疾病的临床试验，部分原因是蛋白质聚集， 作为阿尔茨海默氏症，我们已经制定了一个新的战略和强大的团队努力。这一战略也可以， 更广泛地说，改善了其他神经退行性疾病，其中随意运动受到影响， 其中蛋白质聚集是主要的潜在原因。西尔弗曼博士发现了几种化合物， 细胞中的蛋白质聚集，并具有良好的药代动力学特性，Ozdinler博士开发了一种 使用改善的上运动健康的新型体外和体内临床前药物筛选/验证平台 神经元（UMN）从不同的潜在因素变得患病，作为读出。最近的发现 揭示了在疾病早期改善UMN健康的重要性， UMN健康对于有效的药物发现工作至关重要。不幸的是，这个重要的神经元群体 以前从未在临床前研究中考虑过，即使是通过其选择性识别的疾病， 和进行性退化该提案将开发第一个利用患病UMN的临床前平台 用于评估Silverman实验室产生的抑制蛋白质聚集的新型化合物， 在体外和体内改善患病UMN的健康。在完成这项建议后，我们会动议 沿着沿着两条不同的途径，通过开发一种新的临床前检测方法， 读出，并通过识别与年龄相关的神经退行性疾病的新药， 蛋白质聚集的问题。

Abstract: Recent developments in chemistry, genetics, and biology revealed that many of the age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and ALS/FTD share protein accumulation as the common cause of neuropathology. In addition, the number and kinds of compounds generated within the last years have exponentially increased. However, these developments in science have not yet successfully translated into effective drug discoveries for patients. This proposal is a collaborative project between the Silverman and Ozdinler Labs, blending expertise in medicinal chemistry and selective neuronal vulnerability, respectively. In an effort to expedite drug discovery and to identify novel compounds that can move into clinical trials for ALS and age-related disorders, which develop in part because of protein aggregation, such as Alzheimer's disease, we have developed a novel strategy and a strong team effort. This strategy also could, more broadly, ameliorate other neurodegenerative diseases in which voluntary movement is affected and in which protein aggregation is a major underlying cause. Dr. Silverman discovered several compounds that inhibit protein aggregation in cells and that have favorable pharmacokinetic properties, and Dr. Ozdinler developed a novel in vitro and in vivo preclinical drug screening/verification platform using the improved health of upper motor neurons (UMNs) that become diseased from different underlying factors, as the read-out. Recent discoveries from the Ozdinler group reveal the importance of improving UMN health early in the disease and that maintaining UMN health is crucial for effective drug discovery efforts. It is unfortunate that this important neuron population has never before been considered in preclinical studies, even for diseases that are identified by their selective and progressive degeneration. This proposal will develop the first preclinical platform that utilizes diseased UMNs for the assessment of novel compounds generated in the Silverman lab that inhibit protein aggregation and improve the health of diseased UMNs both in vitro and in vivo. Upon completion of this proposal, we will move the field forward along two different avenues by developing a new preclinical assay that incorporates UMN health as the read-out, and by identifying novel drugs for age-related neurodegenerative diseases that develop from problems with protein aggregation .