Epigenetics In Neurodegenerative Disease: Targeting Histone Modifications in ALS

 描述(申请人提供)：肌萎缩侧索硬化症(ALS)是一种进行性神经退行性疾病，影响大脑和脊髓的细胞。这种毁灭性的致命疾病在任何时候都困扰着大约15,000名美国人。肌萎缩侧索硬化症没有治愈方法，现有的治疗方法也无法控制症状。因此，迫切需要能够快速、安全地治疗肌萎缩侧索硬化症患者的概念上的新疗法。我们的长期目标是了解表观遗传机制在神经退行性疾病病因学中的作用。我们研究的中心假设是组蛋白的翻译后修饰(PTM)在ALS的细胞死亡中起作用。表观遗传学可能揭示疾病发生背后的机制，作为遗传因素和环境因素之间缺失的一环。我们将在两个特定目标下进行这些研究：第一阶段特定目标1：确定ALS中组蛋白的翻译后修饰。在这个目标中，我们将通过Western blotting和MS蛋白质组学来探索ALS患者和他们各自的对照中过量表达FUS和TDP-43的酵母以及诱导的多能干细胞(IPS)的全球表观遗传学组成。这项拟议的工作具有创新性，因为它探索了肌萎缩侧索硬化症生物学中一个研究不足的领域。此外，该项目利用现代技术来解决常规生物化学实验无法解决的问题。为此，我们的工作假设是，组蛋白PTM的变化与ALS中看到的细胞毒蛋白聚集有关。第二阶段具体目标2：探索减轻ALS细胞毒性的化学干预方法在一种独立的方法中，我们将确定靶向表观遗传机制的小分子，这些小分子能够降低ALS iPS细胞的细胞毒性。此外，我将调查这些影响背后的机制的细节。在这个项目完成后，我们预计AIMS 1和AIMS 2中提出的工作组合将揭示在细胞毒蛋白聚集的背景下发挥作用的新的表观遗传机制。这些机制是药物治疗的极易获得的靶点，因此它们可以打开治疗ALS和其他神经退行性疾病的新的替代策略的大门。

 DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects cells in the brain and the spinal cord. This devastating, fatal ailment afflicts about 15,000 Americans at any given time. No cure is available for ALS, and available treatments fail to control symptoms. Owing to this, there is an urgent need for conceptually novel therapies capable of rapidly and safely treating patients suffering from ALS. Our long-term objective is to understand the role of epigenetic mechanisms in the etiology of neurodegenerative disease. The central hypothesis of our research is that posttranslational modification (PTM) of histones has a role in cellular demise in ALS. Epigenetics may reveal a mechanism behind the occurrence of disease, serving as the missing link between genetic and environmental factors. We will pursue these studies in two specific aims: Phase I Specific Aim 1: Determine the Genome-Wide Post-translational Modification of Histones in ALS In this aim, we will explore the global epigenetic make up of both yeast over expressing FUS and TDP- 43 and induced pluripotent stem cells (iPS) from ALS patients and their respective controls through western blotting and mass spectrometry (MS) proteomics. The proposed work is innovative, because it explores an understudied area in the biology of ALS. Furthermore, this project utilizes modern techniques to solve questions inaccessible through conventional biochemical experiments. Our working hypothesis for this aim is that changes on histone PTMs are associated with the cytotoxic protein aggregation seen in ALS. Phase II Specific Aim 2: Explore Chemical Interventions that Lessen ALS Cytotoxicity In an independent approach, we will identify small molecules targeting epigenetic mechanisms that are able to reduce cytotoxicity in ALS iPS cells. Furthermore, I will investigate the details of the mechanisms behind these effects. At the completion of this project, we expect that the combination of work proposed in aims 1 and 2 will uncover novel epigenetic mechanisms at play in the context of cytotoxic protein aggregation. These mechanisms are highly accessible targets for pharmaceutical treatments and thus they can open the door to new, alternative strategies in the treatment of ALS and other neurodegenerative diseases.