Deep Pathological Phenotyping in Frontotemporal Dementia and Motor Neuron Disease.

摘要 该项目旨在对额颞叶痴呆（FTD）和运动性痴呆进行深层病理表型分析。 神经元疾病（MND）。该提案的基本原理是，尽管FTD的基础生物学正在爆炸， 和MND，关于神经变性最强的生物学预测因子的信息有限 在病人的大脑中。更少的是了解潜在的机制，罢工选择性 在FTD和MND中观察到的脆弱性，或者是什么驱动了这两种疾病的临床解剖学重叠。 我们将继续研究这些问题，重点是TAR DNA结合43 kDA（TDP-43）的病理生物学， 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作用 在FTD和MND相关系统中。我们将进一步评估复杂的神经病理学特征 在C9 ORF 72扩增相关FTD/MND中观察到，并构建数据集，以帮助确定 在散发性和C9-FTD/MND的许多病理学特征中， 神经退行性疾病我们的方法旨在克服现有的方法障碍， 先进的组织学，一种新的组织复用平台，允许几十种蛋白质或RNA标记物， 原位定量和单核转录组学。我们将研究FTD/MND中的患者- TDP-43谱，包括C9 ORF 72扩增的受试者和对照受试者。我们的目标是：（1） 将TDP-43病理生物学与核转运缺陷、隐蔽外显子掺入和DNA损伤相关， (2)确定在脆弱的神经元和区域中最普遍的病理变化， 与神经变性密切相关，以及（3）识别神经元脆弱性的转录特征 和FTD/MND中的TDP-43病理生物学。成功完成拟议目标将解决关键问题， 关于FTD/MND-TDP中候选致病机制的人类相关性的问题， 更明智地优先考虑人类治疗开发的潜在靶点。集成 产生的多维数据将创建一个深度库，用于测试新出现的假设 并产生新的假设。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.