Transcriptomic Approaches to TDP-43 Pathology

TDP-43 病理学的转录组学方法

• 批准号: 10454270
• 负责人: Corey T McMillan
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454270
• 关键词: ALS patients; Adult; Aging; Alleles; Amyotrophic Lateral Sclerosis; Anatomy; Antisense Oligonucleotides; Autopsy; Behavioral; Biological; C9ORF72; Cells; Clinical; Complex; DNA; DNA Methylation; DNA Sequence Alteration; Data; Disease; Disease Progression; Epigenetic Process; Evaluation; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Variation; Genotype; Graph; Hereditary Disease; Heterogeneity; Hypermethylation; Image; Individual; Inherited; Investigation; Language Disorders; Length; Link; Magnetic Resonance Imaging; Measurement; Mediating; Methylation; Molecular; Mutation; Nerve Degeneration; Neurocognitive; Neuromuscular Diseases; Pathologic; Pathology; Patients; Pattern; Phenotype; Primary Progressive Aphasia; RNA; RNA-Binding Proteins; Risk; Scanning; Single Nucleotide Polymorphism; Source; Structure; Syndrome; Tars; Therapeutic Intervention; Thick; Variant; adeno-associated viral vector; behavioral variant frontotemporal dementia; burden of illness; control theory; disease phenotype; dosage; education pathway; epigenetic variation; frontotemporal degeneration; frontotemporal lobar dementia-amyotrophic lateral sclerosis; gene therapy; gray matter; in vivo; neuroimaging; neuromuscular; precision medicine; promoter; protein TDP-43; recruit; social deficits; specific biomarkers; superoxide dismutase 1; transcriptomics; white matter

TDP-43 pathological inclusions are associated with a spectrum of clinical syndromes including behavioral variant frontotemporal degeneration (bvFTD), primary progressive aphasia (PPA), or amyotrophic lateral sclerosis (ALS). Moreover, approximately 10% of bvFTD or PPA patients share neuromuscular features of ALS (ALS-FTD). Beyond the clinical complexities of the FTD and ALS spectrum associated with TDP-43, there are also many shared genetic links between these conditions including C9orf72 repeat expansions and TARDBP mutations that can result in bvFTD and/or ALS as well as disparate genetic mutations that exclusively result in FTD (e.g., GRN) or ALS (e.g., SOD1). The overall hypothesis of this project is that molecular heterogeneity, and specifically regionally-variable gene expression, contributes to macroscale network vulnerability contributing to a spectrum of clinically heterogeneous syndromes. It is critical to better understand the neuroanatomic and clinical features of gene expression in the current era of precision medicine in which there are antisense oligonucleotide (ASO) and adeno-associated vector (AAV) viral genetic therapies that aim to modify gene expression which have recently received FDA-approval for neuromuscular disorders and are underway for C9orf72 and GRN. While prior studies suggest that genetic and epigenetic variation contributes to the spectrum of heterogeneity in FTD and ALS, evaluations of the relationships between gene expression and disease phenotype are rare. This project aims to establish biological and genetic factors that influence regional anatomic disease burden which will provide regionally-specific biomarkers to track in emerging genetic therapies. We propose three Specific Aims: (1) Identify regional relationships between molecular gene expression and macroscale networks that bias risk for a specific clinical syndrome. We will interrogate publicly- available regional RNA microarray data and relate patterns of covariance from TDP-associated genes to structurally and functionally-derived networks that are associated with distinct bvFTD, PPA, and ALS syndromes; (2) Establish convergence between gene expression and in vivo neuroimaging networks of FTD and ALS patients. We will relate regional RNA microarray data of healthy individuals to in vivo cortical thickness and graph-theoretic network features (e.g., degree, path length) defined in Core E that are derived from FTD and/or ALS patients with inherited disease recruited from Core B and scanned using 3T MRI in Core C. We hypothesize that the regional distribution of gene covariance in typical adults will relate to the regional distribution of neurodegeneration in individuals with genetic mutations; and (3) Determine the manner in which modifiers of gene expression impact network structure in FTD & ALS. Using principles of network control theory we will leverage naturally-occurring heterogeneity in gene expression, including epigenetic (e.g., DNA methylation) and common genetic (e.g., allele dosage) factors, to determine whether these gene enhancing or silencing sources of heterogeneity are associated with altered network distributions of disease.

TDP-43 病理包涵体与一系列临床综合征相关，包括行为 变异性额颞叶变性 (bvFTD)、原发性进行性失语症 (PPA) 或肌萎缩侧索硬化症 硬化症（ALS）。此外，大约 10% 的 bvFTD 或 PPA 患者具有 ALS 的神经肌肉特征 （ALS-FTD）。除了与 TDP-43 相关的 FTD 和 ALS 谱的临床复杂性之外，还有 这些条件之间还有许多共享的遗传联系，包括 C9orf72 重复扩展和 TARDBP 可能导致 bvFTD 和/或 ALS 的突变，以及专门导致 FTD（例如 GRN）或 ALS（例如 SOD1）。该项目的总体假设是分子异质性， 特别是区域可变的基因表达，导致宏观网络脆弱性 导致一系列临床异质综合征。更好地理解这一点至关重要 当前精准医学时代基因表达的神经解剖学和临床特征 是反义寡核苷酸（ASO）和腺相关载体（AAV）病毒基因疗法，旨在 修改基因表达，最近已获得 FDA 批准用于神经肌肉疾病，并且 C9orf72 和 GRN 正在进行中。虽然先前的研究表明遗传和表观遗传变异有助于 根据 FTD 和 ALS 的异质性范围，评估基因表达之间的关系 且疾病表型很少见。该项目旨在确定影响的生物和遗传因素 区域解剖疾病负担，这将提供区域特异性生物标志物来跟踪新兴遗传疾病 疗法。我们提出三个具体目标：（1）识别分子基因之间的区域关系 表达和宏观网络会偏向特定临床综合征的风险。我们将公开讯问—— 可用的区域 RNA 微阵列数据并将 TDP 相关基因的协方差模式与 与不同的 bvFTD、PPA 和 ALS 相关的结构和功能衍生网络 综合症； (2) 建立FTD基因表达与体内神经影像网络的融合 和 ALS 患者。我们将健康个体的区域 RNA 微阵列数据与体内皮质联系起来 核心 E 中定义的厚度和图论网络特征（例如，度、路径长度）导出 来自从 Core B 招募并使用 Core B 中的 3T MRI 进行扫描的患有遗传性疾病的 FTD 和/或 ALS 患者 C. 我们假设典型成年人基因协方差的区域分布将与区域 具有基因突变的个体中神经退行性疾病的分布； (3) 确定采取何种方式 基因表达修饰因子影响 FTD 和 ALS 中的网络结构。利用网络控制原理 从理论上讲，我们将利用基因表达中自然发生的异质性，包括表观遗传（例如 DNA 甲基化）和常见遗传（例如等位基因剂量）因素，以确定这些基因是否增强或 异质性的沉默来源与疾病网络分布的改变有关。