Deep Pathological Phenotyping in Frontotemporal Dementia and Motor Neuron Disease.

额颞叶痴呆和运动神经元疾病的深层病理表型。

基本信息

批准号：
10449356
负责人：
WILLIAM W SEELEY
金额：
$ 84.82万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449356
关键词：
Affect Anatomy Animal Model Anterior Antisense RNA Atrophic Biological Biology Brain Brain region C9ORF72 Carrier Proteins Cell Nucleus Cells Complex DNA DNA Binding DNA Damage Data Data Set Defect Dipeptides Disease Event Exons Frontotemporal Dementia Gene Expression Gene Expression Profile Genes Genetic Goals Histologic Histology Human Immunofluorescence Immunologic In Situ Individual Lead Libraries Link Measures Methodology Methods Minority Modeling Molecular Motor Neuron Disease Motor Neurons Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Pattern Phenotype RAN GTPase Activating Protein 1 RNA RNA Degradation RNA marker RNA-Binding Proteins Research Stream System Testing Tissues Uncertainty Work base behavioral variant frontotemporal dementia cell type data archive experimental study human disease human tissue innovation insight loss of function multidimensional data neuropathology novel nucleocytoplasmic transport protein TDP-43 protein aggregation protein biomarkers therapeutic development tool transcriptome transcriptome sequencing transcriptomics

项目摘要

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.

抽象的该项目旨在对额颞痴呆（FTD）和运动的深层病理表型进行神经元疾病（MND）。该提案的理由是，尽管FTD的基本生物学爆炸了和MND，有关神经退行性最强生物学预测因子的信息有限在患者的大脑中。关于引人注目的选择性的机制，更少知道在FTD和MND中看到的脆弱性，或者是驱动两种疾病的诊所 - 动物解放重叠的原因。我们将继续进行这些问题，重点是43 kDa（TDP-43）病理学的焦油DNA结合。与其他新兴FTD/MND机制的关系及其针对特定神经元亚型的靶向在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C9ORF72扩展相关的FTD/MND中可见，并构建配备有帮助的数据集以帮助确定哪个在零星和C9-FTD/MND中的许多病理特征中，最强的预测因子神经变性。我们的方法旨在通过结合来克服现有的方法论障碍晚期组织学，一种新型的组织多路复用平台，允许数十种蛋白质或RNA标记原位定量和单核转录组学。我们将研究跨FTD/MND的患者 TDP-43频谱，包括具有C9ORF72膨胀和控制受试者的频谱。我们的目标是：（1）将TDP-43病理生物学与核转运缺陷，隐秘外显子掺入和DNA损伤相关联，（2）确定脆弱神经元和地区最普遍的病理变化，大多数与神经变性密切相关，（3）确定神经元脆弱性的转录特征 FTD/MND中的TDP-43病理生物学。成功完成拟议的目标将解决关键关于FTD/MND-TDP中候选病原机制的人类相关性的问题，启用对人类治疗发展的潜在目标的更明智的优先级。集成产生的多维数据将创建一个深层库，用于测试新假设时出现并用于产生新的假设。最后，实现我们的目标将推动变革性研究神经退行性和其他复杂人类疾病的新组织病理学方法。