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

用于治疗 ALS 和其他神经退行性疾病的新型蛋白质聚集抑制剂和上运动神经元稳定剂

基本信息

批准号：
10624425
负责人：
Pembe Hande Ozdinler
金额：
$ 56.12万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2025-04-30
项目状态：
未结题

项目摘要

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 .

抽象的：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发展疾病，例如肌萎缩性侧面硬化症（ALS），阿尔茨海默氏病和ALS/FTD共享蛋白积累是神经病理学的常见原因。另外，化合物的数量和种类在过去几年中产生的生成成倍增加。但是，这些科学方面的发展尚未然而，成功地转化为患者的有效药物发现。该建议是一个协作项目在Silverman和Ozdinler实验室之间，混合药物化学专业知识和选择性神经元分别脆弱性。为了加快药物发现并识别可以移动的新颖化合物进入ALS和与年龄相关疾病的临床试验，部分原因是蛋白质聚集，这样作为阿尔茨海默氏病，我们制定了一种新颖的策略和强大的团队努力。这个策略也可以，更广泛地，改善其他神经退行性疾病，其中自愿运动受到影响，并在哪种蛋白质聚集是主要的根本原因。西尔弗曼博士发现了几种抑制的化合物细胞中的蛋白质聚集并具有有利的药代动力学特性，Ozdinler博士发展了新颖的体外和体内临床前药物筛查/验证平台，使用上电动机的健康神经元（UMNS）从不同的潜在因素中患病，如读出。最近的发现来自Ozdinler组的来自疾病早期改善UMN健康并保持的重要性 UMN健康对于有效的药物发现工作至关重要。不幸的是，这个重要的神经元人群在临床前研究中从未考虑过，即使对于被其选择性识别的疾病和进行性变性。该建议将开发第一个利用患病UMN的临床前平台为了评估Silverman Lab中产生的新化合物，该化合物抑制蛋白质聚集和改善体外和体内患病的umns的健康状况。完成此提案后，我们将移动通过开发一种新的临床前测定法，将UMN健康纳入两种不同的途径读出，并通过确定与年龄相关的神经退行性疾病的新药物蛋白质聚集的问题。