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: 9336987
• 负责人: Mariana Plazas Torrente
• 金额: $ 15.34万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336987
• 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; Modernization; Modification; Mutation; Neurodegenerative Disorders; Patients; Peptides; Pharmacologic Substance; Phase; Play; Post-Translational Protein Processing; Progressive Disease; Proteins; 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; experimental study; genome-wide; histone modification; improved outcome; induced pluripotent stem cell; inhibitor/antagonist; innovation; motor neuron degeneration; novel; novel therapeutics; overexpression; premature; protein TDP-43; protein aggregate; protein aggregation; protein misfolding; public health relevance; 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（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种影响脑和脊髓细胞的进行性神经退行性疾病。这种毁灭性的致命疾病在任何时候都折磨着大约15,000名美国人。没有治愈ALS的方法，可用的治疗方法无法控制症状。因此，迫切需要能够快速且安全地治疗患有ALS的患者的概念上新颖的疗法。 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，作为遗传和环境因素之间缺失的环节。我们将在两个具体目标下进行这些研究：第一阶段具体目标1：确定ALS中组蛋白的全基因组翻译后修饰在这个目标下，我们将通过蛋白质印迹和质谱（MS）蛋白质组学来探索ALS患者及其各自对照的过表达FUS和TDP- 43的酵母和诱导多能干细胞（iPS）的全球表观遗传组成。这项工作是创新的，因为它探索了ALS生物学中一个未充分研究的领域。此外，该项目利用现代技术解决传统生物化学实验无法解决的问题。我们的工作假设是，组蛋白PTM的变化与ALS中看到的细胞毒性蛋白聚集有关。第二阶段具体目标2：探索减少ALS细胞毒性的化学干预在一种独立的方法中，我们将鉴定出能够降低ALS iPS细胞细胞毒性的靶向表观遗传机制的小分子。此外，我将研究这些影响背后的机制的细节。 在这个项目完成后，我们希望目标1和2中提出的工作组合将揭示在细胞毒性蛋白聚集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高度可及的靶点，因此它们可以为ALS和其他神经退行性疾病的治疗打开新的替代策略的大门。

项目成果

Neurodegenerative Disease Proteinopathies Are Connected to Distinct Histone Post-translational Modification Landscapes.

• DOI: 10.1021/acschemneuro.7b00297
• 发表时间: 2018-04-18
• 期刊: ACS chemical neuroscience
• 影响因子: 5
• 作者: Chen K;Bennett SA;Rana N;Yousuf H;Said M;Taaseen S;Mendo N;Meltser SM;Torrente MP
• 通讯作者: Torrente MP

The impact of histone post-translational modifications in neurodegenerative diseases.

组蛋白翻译后修饰在神经退行性疾病中的影响。

• DOI: 10.1016/j.bbadis.2018.10.019
• 发表时间: 2019-08-01
• 期刊: Biochimica et biophysica acta. Molecular basis of disease
• 作者: Cobos SN;Bennett SA;Torrente MP
• 通讯作者: Torrente MP

Epigenetics in amyotrophic lateral sclerosis: a role for histone post-translational modifications in neurodegenerative disease.

• DOI: 10.1016/j.trsl.2018.10.002
• 发表时间: 2019-03
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Bennett SA;Tanaz R;Cobos SN;Torrente MP
• 通讯作者: Torrente MP