Characterizing Vulnerable Cell Types in C9orf72-FTD

表征 C9orf72-FTD 中的脆弱细胞类型

• 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
• 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

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) 的最常见遗传原因， 致命且无法治愈的神经退行性疾病。 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 神经元和神经胶质细胞中的内含物。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 内含物、神经元 变性和神经炎症，包括病理性小胶质细胞的发育。在其他疾病中， 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。然而，这些 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。 我们假设在 C9-FTLD 中，病理性小胶质细胞导致 兴奋性神经元的脆弱群体，导致痴呆。该提案旨在利用 转录组学方法来识别脆弱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。到 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。蜂窝邻近度是 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 来自痴呆症。这些研究将强调病理性小胶质细胞如何导致神经退行性变， 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。我的 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。