New Targets in C9orf72 FTD: Exploring Histone H3 S10 Phosphorylation

C9orf72 FTD 的新靶点：探索组蛋白 H3 S10 磷酸化

基本信息

批准号：
10359300
负责人：
Mariana Plazas Torrente
金额：
$ 47.1万
依托单位：
BROOKLYN COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10359300
关键词：
Address Affect Age Alzheimer&apos s disease related dementia Amyotrophic Lateral Sclerosis Animals Brain C9ORF72 Cell Death Cell Nucleus Cell Survival Cells ChIP-seq Chromatin DNA Data Degenerative Disorder Dementia Dipeptides Disease Disease Progression Disease model Environment Epigenetic Process Frontotemporal Dementia Gene Expression Gene Expression Regulation Genes Genetic Genomic Segment Genomics Goals Histone H3 Histones Human Immunofluorescence Immunologic Induced pluripotent stem cell derived neurons Investigation Lead Link Mass Spectrum Analysis Mediating Messenger RNA Modeling Modification Molecular Motor Neurons Movement Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Pathway Analysis Pathway interactions Patients Persons Pharmacology Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Process Prognosis Proteins Proteomics Research Role Sampling Scaffolding Protein Serine Temporal Lobe Testing Tissue Model Toxic effect Yeast Model System Yeasts aurora B kinase base college epigenome frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis fused in sarcoma genome-wide graduate student histone modification improved outcome induced pluripotent stem cell inhibitor interest mutant neuroprotection neurotoxicity novel nucleocytoplasmic transport overexpression prevent protein TDP-43 protein aggregation sex undergraduate student

项目摘要

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease that has been linked to disruptions in many genes. FTD belongs to a group of dementias catalogued as Alzheimer's Disease Related Dementias (ADRD). Hexanucleotide repeat expansions in Chromosome 9 Open Reading Frame 72 (C9orf72) are the most common genetic alteration linked to FTD. However, the precise mechanisms linking C9orf72 expansions to neurotoxicity remain incompletely characterized. Histones are the protein scaffold of chromatin. Their post-translational modification can alter gene expression. Our preliminary data support a model of interplay between protein aggregation and histone modifications, a notion that is not well characterized in FTD. We propose the overarching hypothesis that the toxic effect of protein aggregation is related to altered histone marks and altered gene expression. We reveal a genome-wide increase in the phosphorylation of Histone H3 on Serine 10 (H3S10ph), mediated by Aurora B kinase, as an important modification associated with C9orf72 expansions. We propose that C9orf72 mutations lead to increased activity Aurora B kinase in the nucleus which in turn leads to H3S10ph increases causing aberrant gene expression and cell death. Using both yeast overexpression models of C9orf72 and human neuronal models the specific goals of this proposal are to: (1) characterize crosstalk between H3S10ph and other histone modifications; (2) test the role of Aurora B Kinase in cell death; and (3) define the genomic regions impacted by H3S10ph increases. Overall, this research plan will uncover novel epigenetic mechanisms at play in FTD while maintaining our upward research trajectory and enriching the research environment for undergraduate students at Brooklyn College. The long-term benefit of this research is to create a novel mechanistic framework that can lead to new, alternative approaches in the treatment of FTD and other ADRDs.

额颞痴呆（FTD）是一种致命的神经退行性疾病，与中断有关在许多基因中。 FTD属于一组痴呆症，分类为阿尔茨海默氏病有关的痴呆症（ADRD）。六核苷酸在9号染色体开放式阅读框72（C9orf72）中的重复膨胀最多。与FTD有关的常见遗传改变。但是，将C9orf72扩展与神经毒性仍然不完全表征。组蛋白是染色质的蛋白质支架。他们的翻译后修饰可以改变基因表达。我们的初步数据支持蛋白质聚集和组蛋白之间的相互作用模型修改，在FTD中未充分表征的概念。我们提出了一个总体假设蛋白质聚集的毒性作用与组蛋白标记改变和基因表达改变有关。我们揭示一个由Aurora B介导的丝氨酸10（H3S10PH）上组蛋白H3磷酸化的全基因组磷酸化增加激酶，作为与C9ORF72扩展相关的重要修饰。我们建议C9orf72突变导致活性增加的核中Aurora B激酶，进而导致H3S10PH的增加引起异常的基因表达和细胞死亡。使用C9orf72和人类神经元模型该提案的具体目标是：（1）表征H3S10PH之间的串扰和其他组蛋白修饰；（2）测试Aurora B激酶在细胞死亡中的作用；（3）定义基因组受H3S10PH影响的地区增加。总体而言，该研究计划将在FTD中发现新颖的表观遗传机制，同时保持我们向上的研究轨迹，并丰富布鲁克林大学生的研究环境大学。这项研究的长期好处是创建一个新型的机械框架，可以导致新的机械框架 FTD和其他ADRD的治疗方法的替代方法。