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.

项目摘要/摘要 C9ORF72扩张突变是额颞痴呆（C9-FTD）的最常见遗传原因，A 致命和无法治愈的神经退行性疾病。 C9-FTD最常见的是神经病理学的特征 通过额颞Lobar变性（C9-FTLD）和磷酸-TDP-43的积累（PTDP-43） 神经元和神经胶质的夹杂物。在C9-ftld中，介质轨道额皮层（MOFC）在早期受到影响 疾病病程，患有FTD的MOFC病变表观患者患者，表明MOFC 功能障碍会影响FTD临床表型。在疾病中，MOFC表现出PTDP-43夹杂物，神经元 退化和神经炎症，包括病理小胶质细胞的发展。在其他疾病中， 病理小胶质细胞增加细胞外谷氨酸并诱导兴奋性神经元死亡。但是，这些 因素对C9-FTLD发病机理的相对贡献尚不清楚，并且分子特征的分子谱 MOFC中的退化神经元（称为脆弱的神经元）和病理小胶质细胞尚不清楚。 我们假设在C9-FTLD中，病理小胶质细胞有助于选择性变性 兴奋性神经元的脆弱人群，导致痴呆。该建议旨在使用 转录组方法识别脆弱的神经元和病理小胶质细胞亚型，并表征其 可能导致疾病进展的分子谱，空间分布和相互作用。到 此目的，AIM＃1将使用单核RNA测序来识别和表征病理小胶质细胞 出现的亚型和C9-ftld中退化的脆弱神经元亚型。细胞接近是 细胞间相互作用的基础，AIM＃2将使用空间转录组学来识别这些病理的位置 小胶质细胞和脆弱的神经元在空间上分布及其空间近似 其他和PTDP-43夹杂物。 更好地理解C9-FTLD如何改变神经元和小胶质细胞的基因表达模式，它们 空间分布及其相互作用可能导致保护细胞免受疾病和患者的策略 来自痴呆症。这些研究将强调病理小胶质细胞如何有助于神经变性， 为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，我将在组织学和计算技术的使用方面发展专业知识。我的 赞助商爱德华·李（Edward Lee）博士致力于我作为身体科学家的培训和成功。