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Molecular Network Degeneration in FTLD-Related Pathology

FTLD 相关病理学中的分子网络变性

基本信息

批准号：
10625544
负责人：
Edward Byung-Ha Lee
金额：
$ 28.32万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10625544
关键词：
Affect Aging Algorithms Anatomy Anterior Area Autopsy Biochemistry Bioinformatics Biometry Biostatistics Core Brain Brain region Cells Cellular biology Cessation of life Clinical Complex Data Data Set Dementia Disease Disease Progression Experimental Models Frontotemporal Dementia Frontotemporal Lobar Degenerations Gene Expression Genetic Goals Heterogeneity Human Immunohistochemistry Individual Inferior Knowledge Language Ligands Methods Microscopic Molecular Neocortex Network-based Neuroanatomy Neurodegenerative Disorders Neurologic Neurons Nodal Onset of illness Pathologic Pathology Phenotype Primary Progressive Aphasia Resources Series Stereotyping Syndrome System Temporal Lobe Testing Tissues Variant behavioral variant frontotemporal dementia brain tissue cell type cingulate gyrus clinical heterogeneity clinical phenotype design frontal lobe frontotemporal degeneration graph theory grasp human RNA sequencing human data human disease improved molecular phenotype neocortical neuropathology novel protein TDP-43 protein aggregation receptor single-cell RNA sequencing tau Proteins transcriptome sequencing

项目摘要

Dementia is associated with selective degeneration of microscopic and macroscale neuronal networks resulting in heterogeneous clinical features. Data from human neuropathology and experimental models support the hypothesis that neurodegenerative disease pathologies spread through selectively vulnerable neuronal networks. Frontotemporal dementia can manifest clinically as behavioral variant of FTD (bvFTD) or primary progressive aphasia (PPA). Both clinical phenotypes can be associated with the accumulation of protein aggregates in affected brain regions composed of either TDP-43 or tau protein. Understanding how networks degenerate in fronototemporal dementia is important in terms of understanding the progression of disease as it relates to variable clinical and pathologic subtypes. The goal of this project is to perform single cell RNA sequencing (scRNAseq) of key regions that degenerate in frontotemporal lobar degeneration to identify cellular-level molecular networks that are specifically altered due to TDP-43 versus tau pathology in behavioral variant frontotemporal dementia and primary progressive aphasia. Novel bioinformatics approaches will be applied to scRNAseq datasets to identify neuronal cell types and molecular networks which are selectively vulnerable in frontotemporal dementia clinicopathologic subtypes.

痴呆与微观和宏观神经元网络的选择性变性有关导致临床特征异质性。来自人类神经病理学和实验模型的数据支持神经退行性疾病病理通过选择性易感人群传播的假设神经元网络。额颞叶痴呆在临床上可表现为 FTD 行为变异 (bvFTD) 或原发性进行性失语（PPA）。两种临床表型都可能与积累相关受影响的大脑区域中的蛋白质聚集体由 TDP-43 或 tau 蛋白组成。了解如何额颞叶痴呆中的网络退化对于理解痴呆的进展非常重要疾病，因为它与不同的临床和病理亚型有关。该项目的目标是执行单一对额颞叶变性中退化的关键区域进行细胞 RNA 测序 (scRNAseq) 识别由于 TDP-43 与 tau 病理学而特异改变的细胞水平分子网络行为变异型额颞叶痴呆和原发性进行性失语症。新颖的生物信息学方法将应用于 scRNAseq 数据集，以识别神经元细胞类型和分子网络在额颞叶痴呆临床病理亚型中选择性易受影响。