Antibody target identification and novel diagnostics

本项目将重点鉴定特异性识别神经退行性疾病（ND）相关蛋白（如tau、淀粉样蛋白-β（Aβ）、TDP-43、α-突触核蛋白和亨廷顿蛋白（HTT））及其蛋白毒性聚集体的自身抗体。人类自身抗体，其中一些已经在Prücke实验室中鉴定或克隆，还有一些将在该研究单位中新发现，将使用蛋白质微阵列和基于CRISPR/Cas9的流式细胞术方法进行筛选，以鉴定其特异性靶表位。在用生物化学和细胞生物学方法验证自身抗体与其靶标之间的相互作用后，我们将开发高度灵敏的诊断方法，用于检测生物流体中的自身抗体，应用已建立的单分子检测技术。最后，我们的目标是使用我们的合作伙伴提供的样本进行概念验证研究，以检测ND患者血清和/或CSF中潜在的疾病相关人类自身抗体。这里建立的自身抗体靶点发现平台将能够识别与神经退行性疾病高度相关的新型自身抗体表位，并促进开发强大的诊断工具，用于调查，并最终用于临床样本的常规检测。

This project will focus on the identification of autoantibodies that specifically recognize neurodegenerative disease (ND)-associated proteins such as tau, amyloid-beta (Aβ), TDP-43, α-synuclein and huntingtin (HTT) and their proteotoxic aggregate species. Human autoantibodies, some already identified or cloned in the Prüß laboratory and further ones to be newly discovered in this research unit, will be screened with protein microarrays and CRISPR/Cas9-based flow cytometry approaches to identify their specific target epitopes. After validating the interactions between autoantibodies and their targets with biochemical and cell biological methods, we will develop highly sensitive diagnostic assays for detecting autoantibodies in biofluids, applying established single molecule detection technologies. Finally, we aim to perform proof-of-concept studies with samples provided by our collaboration partners to detect potentially disease-relevant human autoantibodies in serum and/or CSF of patients with NDs. The autoantibody-target discovery platform established here will enable the identification of novel autoantibody epitopes with high relevance to neurodegenerative diseases and foster the development of powerful diagnostic tools for investigation, and eventually, routine testing of clinical samples.