Characterizing Vulnerable Cell Types in C9orf72-FTD

表征 C9orf72-FTD 中的脆弱细胞类型

基本信息

批准号：
10464266
负责人：
David Dai
金额：
$ 5.18万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10464266
关键词：
Affect Appearance Autopsy Brain C9ORF72 Cell Nucleus Cells Cessation of life Chromium Complex Computational Technique Data Set Dementia Development Disease Disease Progression Disease associated microglia Environment Exhibits Female Formalin Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional disorder Future Gene Expression Profile Genes Genetic Genomics Glutamates Goals Histological Techniques Histology Human Immunofluorescence Immunologic Immunohistochemistry Individual Induced Mutation Inflammatory Knockout Mice Lead Learning Lesion Location Maps Medial Methods Microglia Molecular Molecular Profiling Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurologist Neurons Paraffin Embedding Pathogenesis Pathologic Patients Phenocopy Phenotype Physicians Population RNA Race Research Scientist Slide Spatial Distribution Stains Techniques Temporal Lobe Testing Tissue Embedding Tissues Training Translational Research Vulnerable Populations cell type clinical phenotype excitatory neuron excitotoxicity extracellular frontal lobe human tissue male neural network neuroinflammation neuron loss novel protein TDP-43 recruit resilience response sex success targeted treatment transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract C9orf72 expansion mutations are the most common genetic cause of frontotemporal dementia (C9-FTD), a fatal and incurable neurodegenerative disease. C9-FTD is most commonly neuropathologically characterized by frontotemporal lobar degeneration (C9-FTLD) and the accumulation of phospho-TDP-43 (pTDP-43) inclusions in neurons and glia. In C9-FTLD, the medial orbitofrontal cortex (mOFC) is affected early in the disease course, and individuals with mOFC lesions phenocopy patients with FTD, suggesting that mOFC dysfunction impacts FTD clinical phenotypes. In disease, the mOFC exhibits pTDP-43 inclusions, neuronal degeneration, and neuroinflammation, including the development of pathologic microglia. In other diseases, pathologic microglia increase extracellular glutamate and induce death in excitatory neurons. However, these factors’ relative contributions to C9-FTLD pathogenesis are not well understood, and the molecular profiles of degenerating neurons (termed vulnerable neurons) and pathologic microglia in the mOFC are unknown. We hypothesize that in C9-FTLD, pathologic microglia contribute to the selective degeneration of vulnerable populations of excitatory neurons, resulting in dementia. This proposal aims to use transcriptomic methods to identify vulnerable neuron and pathologic microglia subtypes and characterize their molecular profiles, spatial distributions, and interactions that may be contributing to disease progression. To this end, Aim #1 will use single-nucleus RNA sequencing to identify and characterize the pathologic microglia subtypes that arise and the vulnerable neuron subtypes that degenerate in C9-FTLD. Cellular proximity is the basis for intercellular interactions, and Aim #2 will use spatial transcriptomics to identify where these pathologic microglia and vulnerable neurons are spatially distributed as well as their spatial proximities in relation to each other and to pTDP-43 inclusions. A better understanding of how C9-FTLD changes neurons’ and microglia’s gene expression patterns, their spatial distributions, and their interactions may lead to strategies to protect cells from disease and patients from dementia. These studies will emphasize how pathologic microglia can contribute to neurodegeneration, enabling the development of microglia-targeted therapies for C9-FTD and other neurodegenerative diseases. Through this project, I will develop expertise in the use of histological and computational techniques. My sponsor, Dr. Edward Lee, is committed to my training and success as a physician-scientist.

项目概要/摘要 C9orf72 扩展突变是额颞叶痴呆 (C9-FTD) 最常见的遗传原因， C9-FTD 是最常见的神经病理学特征。额颞叶变性 (C9-FTLD) 和磷酸化 TDP-43 (pTDP-43) 的积累在 C9-FTLD 中，内侧眶额皮质 (mOFC) 在早期就受到影响。病程以及患有 FTD 的 mOFC 病变表型患者的个体，表明 mOFC 功能障碍影响 FTD 临床表型在疾病中，mOFC 表现出 pTDP-43 包涵体、神经元。变性和神经炎症，包括病理性小胶质细胞的发育。病理性小胶质细胞增加细胞外谷氨酸并诱导兴奋性神经元死亡。因素对 C9-FTLD 发病机制的相对贡献尚不清楚，并且 mOFC 中的退化神经元（称为易损神经元）和病理性小胶质细胞尚不清楚。我们发现，在 C9-FTLD 中，病理性小胶质细胞导致该提案旨在利用兴奋性神经元的脆弱群体，从而导致痴呆症。转录组学方法来识别脆弱的神经元和病理性小胶质细胞亚型并表征它们可能导致疾病进展的分子谱、空间分布和相互作用。为此，目标#1将使用单核RNA测序来识别和表征病理性小胶质细胞 C9-FTLD 中出现的亚型和退化的脆弱神经元亚型是细胞邻近性。细胞间相互作用的基础，目标#2将使用空间转录组学来确定这些病理性的位置小胶质细胞和脆弱神经元在空间上分布以及它们与每个神经元的空间邻近性其他和 pTDP-43 内含物。更好地了解 C9-FTLD 如何改变神经元和小胶质细胞的基因表达模式及其空间分布及其相互作用可能会导致保护细胞免受疾病和患者侵害的策略这些研究将强调病理性小胶质细胞如何导致神经变性，促进针对 C9-FTD 和其他神经退行性疾病的小胶质细胞靶向疗法的开发。通过这个项目，我将发展组织学和计算技术使用方面的专业知识。赞助商爱德华·李博士致力于我作为一名医师科学家的培训和成功。