Shared and disparate genomic features of TDP-43 proteinopathies

TDP-43 蛋白病共有和不同的基因组特征

基本信息

批准号：
10537655
负责人：
Barbara Elizabeth Spencer
金额：
$ 6.76万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2022-08-19 至 2025-08-18
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537655
关键词：
Amyotrophic Lateral Sclerosis Attenuated Automobile Driving Autopsy Behavioral Bioinformatics Biological Brain C9ORF72 Characteristics Clinical Cognitive Complex DNA Binding DNA Sequence Alteration Data Dementia Development Disease Family Foundations Frontotemporal Lobar Degenerations Functional disorder Gene Expression Genes Genetic Genetic Variation Genomics Genotype Heterogeneity Immunohistochemistry Impaired cognition Individual Link Measures Medical Genetics Mentorship Molecular Motor Cortex Motor Neurons Mutation Nerve Degeneration Neurodegenerative Disorders Pathologic Pathology Pattern Phenotype Predisposition Quantitative Trait Loci Research Support Risk Sampling Signal Transduction Single Nucleotide Polymorphism Syndrome Temporal Lobe Testing Tissue Sample Tissue-Specific Gene Expression Tissues Training Transcriptional Regulation Variant Weight Work behavioral impairment case control causal variant cell type clinical heterogeneity differential expression digital disorder risk experience frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis functional genomics genetic association genetic risk factor genetic variant genome wide association study genomic locus insight neuromuscular neuropathology novel novel strategies polygenic risk score protein TDP-43 regional difference risk variant statistics superoxide dismutase 1 therapeutic development therapeutic target trait transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract TAR DNA-binding ~43kDa (TDP-43) inclusions are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). Despite shared pathological features, ALS and FTLD-TDP can present with heterogenous clinical features including cognitive/behavioral impairments (i.e., FTLD-TDP), motor neuron dysfunction (i.e., ALS), or both (i.e., ALS-FTD). Moreover, certain genetic mutations typically only result in ALS or FTLD-TDP, but other mutations can cause FLTD-TDP and/or ALS within the same family. Together, the shared and disparate pathological, clinical, and genetic features of FTLD-TDP, ALS, and ALS-FTD support the notion that they are part of a clinicopathologic spectrum. However, the vast majority of ALS and FTLD-TDP cases are considered sporadic and have no known causal mutation. The underlying molecular mechanisms that contribute to the observed clinical heterogeneity across sporadic TDP-43 proteinopathies are not well understood. Supporting evidence for a genetic component to sporadic cases, common genetic variants have been associated with disease risk for either ALS or FTLD-TDP. However, combined studies across TDP-43 proteinopathies are rare. Thus, the extent to which risk alleles are shared or disparate across these phenotypes is unclear. While there is mounting evidence of shared genetic factors that explain the biological mechanisms that drive susceptibility to both diseases, considerably less effort has focused on the disparate genetic features across TDP-43 proteinopathies. Identifying disparate variants may contribute to our understanding of disease-specific drivers. The first aim of this proposal is to identify both the shared and disparate genomic features that drive individual-level cognitive/behavioral and/or neuromuscular presentations of these syndromes. TDP-43 pathology and neurodegeneration are observed in characteristic neuroanatomical regions that correlate with the clinical presentations of ALS and FTLD-TDP, but it is unclear what contributes to this regional selective vulnerability. Previous work has demonstrated clear regional differences in gene expression within the same individuals. Gene expression quantitative trait loci analyses can identify genomic loci that explain variation in gene expression. However, these associations are highly tissue and cell type specific, which may obscure important differences. This is especially true within neurodegenerative disorders, as observed gene expression differences may reflect cell type composition differences rather than true transcriptional regulation. The second aim of this proposal is to investigate genetic contributions to regionally specific differential gene expression, including cell type specific expression, in ALS and FTLD-TDP. Overall, this proposal leverages genotype and transcriptomic approaches to understand molecular contributions of regional selective vulnerability in ALS and FTLD-TDP. In disentangling this heterogeneity, it may be possible to inform efforts to develop therapeutic targets that attenuate the course of these neurodegenerative diseases.

项目摘要/摘要焦油DNA结合〜43KDA（TDP-43）夹杂物是额颞叶的病理标志 TDP-43（FTLD-TDP）和肌萎缩性侧硬化症（ALS）的变性。尽管有共同的病理特征，ALS和FTLD-TDP可以具有异质临床特征，包括认知/行为障碍（即FTLD-TDP），运动神经元功能障碍（即ALS）或两者（即ALS-FTD）。而且，可以肯定基因突变通常仅导致ALS或FTLD-TDP，但其他突变会导致FLTD-TDP和/或同一家庭中的ALS。一起，共享和不同的病理，临床和遗传特征 FTLD-TDP，ALS和ALS-FTD支持它们是临床病理谱系的一部分的观念。然而，绝大多数ALS和FTLD-TDP病例被认为是零星的，没有已知的因果突变。有助于观察到的临床异质性的基本分子机制 TDP-43蛋白质病尚不清楚。支持遗传成分零星的证据病例，常见的遗传变异与ALS或FTLD-TDP的疾病风险有关。然而，跨TDP-43蛋白质病的联合研究很少见。因此，风险等位基因的程度在这些表型中共享或不同的是不清楚的。虽然有共同遗传的越来越多的证据解释引起两种疾病敏感性的生物学机制的因素，努力少得多专注于TDP-43蛋白质病的不同遗传特征。识别不同的变体可能有助于我们对疾病特异性驱动因素的理解。该提议的第一个目的是确定共享和不同的基因组特征，这些特征驱动个人级别的认知/行为和/或这些综合征的神经肌肉表现。 TDP-43病理和神经退行性在与ALS和FTLD-TDP的临床表现相关的特征神经解剖区域，但目前尚不清楚有什么促进这种区域选择性脆弱性的原因。以前的工作已经表现出清晰的同一个体内基因表达的区域差异。基因表达定量性状基因座分析可以鉴定出解释基因表达变异的基因组基因座。但是，这些关联是高度组织和细胞类型的特异性可能会掩盖重要的差异。在内部尤其如此神经退行性疾病，因为观察到的基因表达差异可能反映了细胞类型的组成差异而不是真正的转录调节。该提议的第二个目的是研究遗传 ALS中对区域特异性差异基因表达的贡献，包括细胞类型特异性表达和FTLD-TDP。总体而言，该建议利用基因型和转录组方法来理解 ALS和FTLD-TDP中区域选择性脆弱性的分子贡献。在解开这一点异质性，有可能告知努力开发衰减过程的治疗靶标这些神经退行性疾病。