Characterizing Vulnerable Cell Types in C9orf72-FTD

项目总结/摘要 C9 orf 72扩展突变是额颞叶痴呆（C9-FTD）最常见的遗传原因， 致命且无法治愈的神经退行性疾病。C9-FTD最常见的神经病理学特征 通过额颞叶变性（C9-FTLD）和磷酸-TDP-43（pTDP-43）的积累， 神经元和神经胶质中的内含物。在C9-FTLD中，内侧眶额皮质（mOFC）在早期受到影响， 病程和mOFC病变个体与FTD患者表型相似，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，神经元包涵体， 变性和神经炎症，包括病理性小胶质细胞的发展。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。但这些 因子对C9-FTLD发病机制的相对贡献尚不清楚， mOFC中的退化神经元（称为脆弱神经元）和病理性小胶质细胞是未知的。 我们假设在C9-FTLD中，病理性小胶质细胞有助于选择性变性。 易受伤害的兴奋性神经元群体，导致痴呆症。该提案旨在利用 转录组学方法来鉴定脆弱神经元和病理性小胶质细胞亚型并表征其 分子谱、空间分布和可能导致疾病进展的相互作用。到 为此，目标1将使用单核RNA测序来鉴定和表征病理性小胶质细胞 C9-FTLD中出现的脆弱神经元亚型和退化的脆弱神经元亚型。细胞接近度是 目标2将使用空间转录组学来确定这些病理性的 小胶质细胞和脆弱的神经元是空间分布的，以及它们相对于每个神经元的空间接近性。 其他和pTDP-43夹杂物。 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， 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影响的策略 得了痴呆这些研究将强调病理性小胶质细胞如何导致神经变性， 从而能够开发针对C9-FTD和其他神经退行性疾病的小胶质细胞靶向疗法。 通过这个项目，我将发展组织学和计算技术的使用专业知识。我 赞助商，爱德华·李博士，致力于我的训练和成功，作为一个医生科学家。

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.