Single-Cell Transcriptional and Epigenomic Dissection to Identify Therapeutic Targets for ALS and FTD

单细胞转录和表观基因组解剖以确定 ALS 和 FTD 的治疗靶点

基本信息

批准号：
10611319
负责人：
Veronique Belzil
金额：
$ 73.32万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611319
关键词：
ALS patients Address Adult Affect Amyotrophic Lateral Sclerosis Astrocytes Autopsy Bayesian Method Biological Brain Brain Pathology Brain region CRISPR screen Candidate Disease Gene Cell model Cells Clinical Coculture Techniques Communities Complex DNA Data Data Set Development Disease Dissection Distal Enhancers Epigenetic Process Frontotemporal Lobar Degenerations Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Transcription Genetic Variation Human Individual Induced pluripotent stem cell derived neurons Link Maps Mediating Mediation Modeling Molecular Motor Cortex Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Nucleic Acid Regulatory Sequences Pathologic Pathway interactions Patients Phenotype Prefrontal Cortex Regulatory Element Resolution Resources Sampling Single Nucleotide Polymorphism Techniques Therapeutic Intervention Transcription Alteration Untranslated RNA Variant career cell type differential expression epigenomic profiling epigenomics experimental study frontotemporal lobar dementia amyotrophic lateral sclerosis genetic information genetic signature genome wide association study genomic locus induced pluripotent stem cell insight middle age new therapeutic target novel novel therapeutic intervention predictive signature prevent promoter risk variant single-cell RNA sequencing therapeutic target trait transcriptome

项目摘要

Abstract Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are devastating and fatal neurodegenerative diseases that strike middle-aged adults just as they reach full familial, financial and career potential. Initially thought to be quite distinct, FTLD and ALS are now recognized to share many clinical, pathological, and genetic signatures, but the mechanistic basis of their shared and distinct circuitry remains unknown at the molecular level. Genome-wide association studies (GWAS) have uncovered multiple common weak-effect variants, but the vast majority are non-coding, making it difficult to identify their target genes and the cell types where they act. To address this challenge, in Aim 1, we systematically profile the transcriptional and epigenomic alterations of FTLD and ALS patients at single-cell resolution using post-mortem brain samples. In Aim 2, we integrate the resulting datasets to study the link between genetic, epigenomic, transcriptional, and cellular signatures of FTLD and ALS, and to study the common and distinct genes and pathways altered in each, to predict new therapeutic targets. In Aim 3, we validate the molecular and cellular effects of these targets using high-throughput directed perturbation experiments and both cell-autonomous and non-autonomous phenotypes guided by our predicted pathways, and we disseminate all our results to the community. The resulting datasets, analyses, and validated targets will provide an invaluable resource to understand the mechanisms of action of FTLD and ALS, and the common and unique circuitry towards new therapeutic targets.

抽象的额颞叶变性 (FTLD) 和肌萎缩侧索硬化症 (ALS) 具有毁灭性和致命性神经退行性疾病袭击中年人，他们刚刚步入家庭、财务和事业的巅峰潜在的。 FTLD 和 ALS 最初被认为是截然不同的，但现在被认为有许多共同的临床、病理和遗传特征，但它们共享和独特电路的机械基础仍然存在在分子水平上未知。全基因组关联研究（GWAS）发现了多种常见的弱效应变体，但绝大多数是非编码的，因此很难识别其目标基因和它们起作用的细胞类型。为了应对这一挑战，在目标 1 中，我们系统地分析了转录使用死后大脑以单细胞分辨率观察 FTLD 和 ALS 患者的表观基因组变化样品。在目标 2 中，我们整合所得数据集来研究遗传、表观基因组、 FTLD 和 ALS 的转录和细胞特征，并研究共同和独特的基因和每个通路都发生改变，以预测新的治疗靶点。在目标 3 中，我们验证了分子和细胞使用高通量定向扰动实验以及细胞自主和由我们预测的途径引导的非自主表型，并且我们将所有结果传播给社区。由此产生的数据集、分析和经过验证的目标将为了解 FTLD 和 ALS 的作用机制，以及新的共同和独特的电路治疗目标。