Pathologically modified TDP-43 in neurodegenerative diseases

病理修饰的 TDP-43 在神经退行性疾病中的应用

基本信息

批准号：
8093934
负责人：
Tania France Gendron
金额：
$ 23.25万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8093934
关键词：
Age Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Antibodies Biological Biological Assay Biological Markers Brain Brain Pathology C-terminal Cerebrospinal Fluid Cleaved cell Clinical Clinical Management Clinical Research Clinical Trials Data Deposition Detection Development Diagnosis Diagnostic Disease Disease Progression Early Diagnosis Enzyme-Linked Immunosorbent Assay Evaluation Face Frontotemporal Dementia Frontotemporal Lobar Degenerations Future Gender Genes Goals Heterogeneity Impaired cognition Individual Investigational Therapies Link Liquid substance Longitudinal Studies Measurement Measures Metric Molecular Monitor Monoclonal Antibodies Motor Motor Neuron Disease Mutation Nerve Degeneration Neurodegenerative Disorders Oryctolagus cuniculus Pathogenesis Pathology Patients Plasma Pulmonary function tests Resources Sampling Severity of illness Sex Characteristics Testing Therapeutic Ubiquitin Variant age difference assay development base clinical application clinically significant cost disease diagnosis disease phenotype drug efficacy effective therapy improved molecular marker muscle strength novel polyclonal antibody prospective protein TDP-43 stem tau Proteins therapeutic target tool treatment response

项目摘要

DESCRIPTION (provided by applicant): TDP-43 is the principal component of ubiquitin-positive inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Mutations in the gene encoding TDP-43 have been identified in ALS and FTLD with or without motor neuron disease, providing a direct link between TDP-43 and neurodegeneration. Of note, TDP-43 pathology is observed to varying degrees in other neurodegenerative disorders. For instance, TDP-43 inclusions are present in up to 56% of Alzheimer's disease (AD) cases. As with ALS and FTLD-U, the cytosolic deposition of TDP-43 in AD is associated with the presence of abnormally phosphorylated TDP-43 (pTDP-43) and C-terminal TDP-43 fragments (cTDP). Compared to AD patients without TDP-43 pathology, those with TDP-43 pathology are cognitively and functionally worse, suggesting that abnormal TDP-43 causes a modified AD phenotype. Therapeutics that target TDP-43 may thus prove beneficial for this subset of AD patients in addition to ALS and FTLD-U patients. As treatments are investigated, it is essential to prepare for diagnostic issues that will arise when compounds are ready for clinical trials. In the evaluation of new treatments for ALS, FTLD-U and AD, it would be advantageous to be able to distinguish between patients with and without TDP-43 pathology. Thus, the development of antemortem assays that recognize TDP-43 proteinopathies is greatly needed. Moreover, the refinement of biomarker assays is a key strategy, not only for aiding with diagnosis of disease, but also for generating more sensitive measures of disease activity and progression. We hypothesize that the presence of TDP-43-positive inclusions in ALS, FTLD-U and AD suggests that TDP-43 levels in cerebrospinal fluid (CSF) and plasma will parallel TDP-43 brain pathology. Moreover, we believe that the sensitivity and utility of TDP-43 as a biomarker may be enhanced by developing enzyme-linked immunosorbent assays (ELISAs) that detect pathological forms of TDP-43, such as pTDP-43 and cTDP. Therefore, we generated polyclonal antibodies towards pTDP-43 and cTDP and propose to produce similar monoclonal antibodies, as these are critical for the development of reproducible assays with future clinical applications. Using our novel antibodies, we aim to develop sensitive ELISAs for the detection of total and pathological TDP-43 which will be used, together with immunohistochemical analysis of brain TDP-43 pathology, to assess whether pathologically modified TDP-43 in CSF and/or plasma is a reliable indicator of brain TDP-43 pathology in ALS, FTLD-U and AD. Importantly, given that longitudinal data is very limited, we will use both plasma and CSF collected longitudinally from ALS patients to examine pathological TDP-43 levels in relation to clinical presentation and rate of disease progression. PUBLIC HEALTH RELEVANCE: The refinement of biomarkers is a key strategy for elucidating the pathogenesis of neurodegenerative diseases and for developing sensitive measures of disease activity and progression. Overall, the goals of this project are to generate sensitive assays to measure pathologically modified TDP-43 in biological fluids and to validate their use as an urgently needed tool for diagnosing and monitoring the progression of TDP-43 proteinopathies, like amyotrophic lateral sclerosis, frontotemporal dementia with ubiquitin-positive inclusions and Alzheimer's disease cases having TDP-43 pathology. Ultimately, such antemortem assays will provide a molecular basis for improving the early diagnosis of TDP-43 proteinopathies, which is important for the correct clinical management of patients, as well as provide a more efficient and objective evaluation of experimental therapies in clinical trials.

描述（由申请人提供）：TDP-43是肌萎缩性外侧硬化症（ALS）（ALS）和额叶LOBAR变性（ubiquitin阳性包含率（FTLD-U））的主要成分。编码TDP-43的基因中的突变已在ALS和FTLD中鉴定出有或没有运动神经元疾病的FTLD，提供了TDP-43与NeuroDegeneration之间的直接联系。值得注意的是，在其他神经退行性疾病中观察到TDP-43病理的不同程度。例如，在阿尔茨海默氏病（AD）病例的56％中，TDP-43夹杂物存在。与ALS和FTLD-U一样，TDP-43在AD中的胞质沉积与存在异常磷酸化的TDP-43（PTDP-43）和C端TDP-43片段（CTDP）有关。与没有TDP-43病理的AD患者相比，患有TDP-43病理学的患者在认知上和功能上更糟，这表明异常TDP-43引起了修改的AD表型。因此，针对TDP-43的靶向TDP-43的疗法除了ALS和FTLD-U患者外，还可以证明对AD患者的这一子集有益。随着治疗的研究，必须准备准备诊断问题，这些诊断问题是在准备临床试验的化合物时会出现的。在评估ALS，FTLD-U和AD的新治疗方法时，能够区分和没有TDP-43病理的患者将是有利的。因此，非常需要识别TDP-43蛋白质病的动物结构测定法的发展。此外，生物标志物分析的完善是一种关键策略，不仅是为了帮助诊断疾病，而且还用于产生更敏感的疾病活动和进展。我们假设在ALS，FTLD-U和AD中存在TDP-43阳性夹杂物的存在表明，脑脊液（CSF）和等离子体中的TDP-43水平将平行于TDP-43脑病理学。此外，我们认为，可以通过开发酶联免疫吸附测定法（ELISA）来增强TDP-43作为生物标志物的敏感性和实用性，从而检测TDP-43的病理形式，例如PTDP-43和CTDP。因此，我们对PTDP-43和CTDP产生了多克隆抗体，并提出生产类似的单克隆抗体，因为这些抗体对于开发具有未来临床应用的可再现测定法至关重要。使用我们的新抗体，我们旨在开发敏感的ELISA来检测总和病理TDP-43，该抗体将与脑TDP-43病理学的免疫组织化学分析一起使用，以评估病理修饰的TDP-43在CSF和/或等化中是否可靠地指示了脑TDP-43 Pathlogy and ALS ALS，FTILD，FTILD。重要的是，鉴于纵向数据非常有限，我们将同时使用ALS患者纵向收集的血浆和CSF来检查与临床表现和疾病进展率有关的病理TDP-43水平。公共卫生相关性：生物标志物的完善是阐明神经退行性疾病的发病机理以及开发敏感疾病活动和进展敏感的措施的关键策略。总体而言，该项目的目标是生成敏感的测定，以测量生物流体中病理修饰的TDP-43，并验证其用作静止需要的工具，用于诊断和监测TDP-43蛋白质病的进展，例如伴有肌萎缩性的侧面粘膜，额外疾病的肾上腺素痴呆症，并具有尿位蛋白伴有尿位蛋白症状， TDP-43病理学。最终，此类动物符号测定将为改善TDP-43蛋白质病的早期诊断提供分子基础，这对于对患者的正确临床治疗非常重要，并提供了对临床试验中实验疗法的更有效和客观评估。