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

基本信息

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
项目类别：
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

项目摘要

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（申请人）：肌萎缩性的侧面硬化症（ALS）是脊髓的，致命的，致命的疾病在任何给定的时间都遭受了约15,000名美国人长期目的是了解表观遗传机制在神经退行性疾病的病因中的作用。在两个具体目的中进行研究：第一阶段特定目标1：确定组蛋白M的全基因组翻译后修饰，我们将探索全球表观表观遗传学构成Op Op Op Op Op op op op op yeast yeast在表达FUS和TDP-43方面，并诱导了多能茎ALS患者及其各自的剧院蛋白质印迹（MS）的细胞（IPS）是创新的，因为它探索了ALS生物学中的一个研究区域在ALS中看到的细胞毒性蛋白质聚集。新型的表观遗传机制在细胞毒性蛋白的一致性中发挥作用。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.