Epigenetics In Neurodegenerative Disease: Targeting Histone Modifications in ALS

神经退行性疾病中的表观遗传学：针对 ALS 中的组蛋白修饰

• 批准号: 8869120
• 负责人: Mariana Plazas Torrente
• 金额: $ 5.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2015-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869120
• 关键词: Affect; American; Amyotrophic Lateral Sclerosis; Antibodies; Area; Biochemical; Biological Assay; Biology; Brain; Categories; Cell Survival; Cells; Chemicals; Disease; Drug Targeting; Environmental Risk Factor; Enzymes; Epigenetic Process; Epitopes; Etiology; Familial Amyotrophic Lateral Sclerosis; Generations; Genes; Genetic; Goals; Histones; Human; Inclusion Bodies; Individual; Inherited; Intervention; Link; Mass Spectrum Analysis; Methods; Modeling; Modification; Mutation; Neurodegenerative Disorders; Outcome; Patients; Peptides; Pharmacologic Substance; Phase; Play; Post-Translational Protein Processing; Progressive Disease; Proteomics; RNA-Binding Proteins; Research; Role; Spinal Cord; Symptoms; Techniques; Time; Toxic effect; Validity of Results; Variant; Western Blotting; Work; Yeasts; base; cellular development; chromatin remodeling; cross reactivity; cytotoxic; cytotoxicity; genome-wide; histone modification; improved; induced pluripotent stem cell; inhibitor/antagonist; innovation; motor neuron degeneration; novel; overexpression; premature; protein TDP-43; protein aggregation; protein misfolding; public health relevance; research study; small molecule; trait

 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.

 描述（由适用提供）：肌萎缩性侧索硬化症（ALS）是一种进行性神经退行性疾病，会影响大脑和脊髓中的细胞。这种毁灭性的致命疾病在任何给定时间都会困扰约15,000名美国人。无法治愈ALS，可用的治疗方法无法控制症状。因此，迫切需要在概念上进行新型疗法，能够快速安全地治疗患有ALS的患者。我们的长期目标是了解表观遗传机制在神经退行性疾病的病因中的作用。我们研究的中心假设是，组蛋白的翻译后修饰（PTM）在ALS中的细胞衰减中起作用。表观遗传学可能会揭示出疾病发生的机制，这是遗传因素与环境因素之间缺失的联系。我们将以两个具体的目的进行这些研究：第一阶段特定目的1：在此目标中确定ALS中组蛋白的整个基因组翻译后修饰，我们将探索酵母在表达FUS和TDP-43的全球表观遗传学组成，并通过Als患者和他们的群体群（MS）（MS）（IPS）和群落（IPS）诱导的多能干细胞（IPS）和群体（MS）（MS）（MS）（IPS）。拟议的工作是创新的，因为它探索了ALS生物学中的一个知识领域。此外，该项目利用现代技术来通过传统的生化实验来解决无法访问的问题。我们针对此目的的工作假设是，组蛋白PTM的变化与ALS中看到的细胞毒性蛋白聚集有关。 II期特异性目标2：探索化学干预措施，以独立方法降低ALS细胞毒性，我们将确定针对表观遗传机制的小分子，这些分子能够降低ALS IPS细胞中的细胞毒性。此外，我将研究这些效果背后的机制细节。该项目完成后，我们预计目标1和2中提出的工作的组合将在细胞毒性蛋白聚集的背景下发现新颖的表观遗传机制。这些机制是药物治疗的高度可进入的靶标，因此它们可以为治疗ALS和其他神经退行性疾病的新替代策略打开大门。