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病理夹杂物与一系列临床综合症有关 变体额颞变性（BVFTD），主要进行性失语（PPA）或肌萎缩性侧面 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光谱的临床复杂性外，还有 同样，这些条件之间的许多共享遗传联系，包括C9orf72重复扩展和TARDBP 可能导致BVFTD和/或ALS以及不同的基因突变的突变，仅导致 FTD（例如GRN）或ALS（例如SOD1）。该项目的总体假设是分子异质性， 特别是区域变化的基因表达，有助于宏观网络脆弱性 导致一系列临床异质综合症。更好地了解 在当前的精密医学时代，基因表达的神经解剖学和临床特征在其中 是反义寡核苷酸（ASO）和腺相关载体（AAV）病毒遗传疗法，目的是 修改基因表达，最近接受了神经肌肉疾病的FDA批准，并且 C9orf72和GRN的正在进行中。虽然先前的研究表明遗传和表观差异有助于 对于FTD和ALS的异质性的光谱，对基因表达之间关系的评估 和疾病表型很少见。该项目旨在建立影响影响的生物学和遗传因素 区域解剖疾病负担将提供特定于区域的生物标志物，以追踪新兴的遗传 疗法。我们提出了三个具体目的：（1）确定分子基因之间的区域关系 表达和宏观网络偏向特定临床综合征的风险。我们将公开询问 - 可用的区域RNA微阵列数据，并将协方差从TDP相关基因与 与不同的BVFTD，PPA和ALS相关的结构和功能衍生的网络 综合征； （2）在FTD的基因表达与体内神经影像网络之间建立收敛 和ALS患者。我们将将健康个体的区域RNA微阵列数据与体内皮质联系在一起 厚度和图理论网络特征（例如，程度，路径长度）在核心E中定义的，这些特征是核心E的定义的 从核心B募集的FTD和/或ALS患者，并使用3T MRI扫描核心 C.我们假设基因协方差在典型成年人中的区域分布将与区域有关 神经退行性的分布在具有基因突变的个体中； （3）确定的方式 FTD＆ALS中基因表达影响网络结构的修饰符。使用网络控制原理 理论我们将利用基因表达中的自然异质性，包括表观遗传学（例如，DNA 甲基化）和常见的遗传（例如等位基因剂量）因素，以确定这些基因是增强还是 沉默的异质性来源与疾病网络分布的改变有关。