Deep Pathological Phenotyping in Frontotemporal Dementia and Motor Neuron Disease.

摘要 该项目旨在对额颞叶痴呆(FTD)和运动进行深入的病理表型分析 神经元疾病(MND)。这项提议的理由是，尽管FTD的基础生物学正在爆炸式增长 此外，关于神经退行性变的最强生物学预测因子的信息有限 在病人的大脑中。更不知道的是，这种突击选择背后的机制 在FTD和MND中看到的脆弱性，或者是什么原因导致这两种疾病的临床解剖重叠。 我们将以43KDA(TDP-43)病理生物学的TAR DNA结合为重点来探讨这些问题 与其他新出现的FTD/MND机制的关系及其对特定神经元亚型的靶向 在与FTD和MND相关的系统内。我们将进一步评估复杂的神经病理特征。 在C9ORF72扩展相关的FTD/MND中可见，并构建数据集以帮助确定 在散发性和C9-FTD/MND的众多病理特征中，预测最强的是C9-FTD/MND 神经退行性变。我们的方法试图克服现有的方法障碍，通过结合 先进组织学，一种新的组织多路传输平台，允许数十个蛋白质或RNA标记 进行原位定量，并进行单核转录。我们将研究FTD/MND的患者- TDP-43谱，包括C9ORF72扩张者和对照受试者。我们的目标是：(1) 将TDP-43病理生物学与核运输缺陷、隐蔽外显子掺入和DNA损伤联系起来， (2)确定最易受伤害的神经元和区域以及大多数 与神经退行性变密切相关，以及(3)识别神经元脆弱性的转录特征 和TDP-43在FTD/MND中的病理生物学特征。成功完成拟议的目标将解决关键问题 关于FTD/MND-TDP候选致病机制与人类相关性的问题，使 更明智地确定人类治疗开发的潜在目标的优先顺序。集成的 产生的多维数据将创建一个深度库，用于在新假设出现时对其进行测试 以及产生新的假设。最后，实现我们的目标将推动一个变革性的 研究神经退行性疾病和其他复杂人类疾病的新组织病理学方法。

Abstract This project seeks to perform deep pathological phenotyping of frontotemporal dementia (FTD) and motor neuron disease (MND). The rationale for the proposal is that, despite the exploding basic biology of FTD and MND, limited information is available about the strongest biological predictors of neurodegeneration in the brains of patients. Even less is known about mechanisms underlying the striking selective vulnerability seen in FTD and MND or what drives the clinico-anatomical overlap of the two disorders. We will pursue these questions with a focus on TAR DNA-binding of 43 kDA (TDP-43) pathobiology, its relationship to other emerging FTD/MND mechanisms, and its targeting of specific neuronal subtypes within the FTD- and MND-related systems. We will further evaluate the complex neuropathological profile seen in C9ORF72 expansion-related FTD/MND and build datasets equipped to help determine which among the many pathological features in sporadic and C9-FTD/MND represent the strongest predictors of neurodegeneration. Our approach seeks to overcome existing methodological barriers by combining advanced histology, a novel tissue multiplexing platform that allows dozens of protein or RNA markers to be quantified in situ, and single nucleus transcriptomics. We will study patients across the FTD/MND- TDP-43 spectrum, including those with the C9ORF72 expansion, and control subjects. We aim to: (1) Relate TDP-43 pathobiology to nuclear transport defects, cryptic exon incorporation, and DNA damage, (2) Determine the pathological changes most prevalent in vulnerable neurons and regions and most strongly linked to neurodegeneration, and (3) Identify transcriptional signatures of neuronal vulnerability and TDP-43 pathobiology in FTD/MND. Successful completion of the proposed aims would resolve key questions about the human relevance of candidate pathogenic mechanisms in FTD/MND-TDP, enabling more informed prioritization of potential targets for human therapeutic development. The integrated multidimensional data produced would create a deep library for testing new hypotheses as they emerge and for generating new hypotheses. Finally, accomplishing our goals would advance a transformative new histopathological approach to studying neurodegenerative and other complex human diseases.