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.