Scanning for intensely fluorescent targets (SIFT): a new tool to study pathological protein aggregate formation in MFM and its reversal through pharmacologic intervention

扫描强荧光靶标 (SIFT)：一种研究 MFM 中病理蛋白聚集体形成及其通过药物干预逆转的新工具

• 批准号: 149382979
• 负责人: Professorin Dr. Maggie C. Walter
• 金额: --
• 依托单位: Zentrum für Neuropathologie und Prionforschung
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/149382979?language=en
• 关键词: Scanning; intensely; fluorescent; targets; SIFT

We aim to elucidate the mechanisms leading to pathological protein aggregation and muscle pathology in myofibrillar myopathies due to mutations in MFM causing genes. As a novel approach, we will use multi-color confocal single-particle spectroscopy methods such as scanning for intensely fluorescing targets (SIFT) to analyze protein aggregates of desmin mutants and other MFM-associated proteins, which have previously been characterized by transfection and in vitro assembly studies. The focus will be the characterization of pathological protein aggregates in regard to formation, molecular architecture, and homologeous as well as heterologeous protein-protein interactions in living cells and at the single-molecule level. Therapeutic perspectives are addressed by testing novel compounds directly targeting pathological protein oligomers, allelle-specific knock-down, heat shock protein inducers, and compounds affecting aggregate clearance by autophagy and proteasomal metabolism.

我们的目的是阐明机制，导致病理性蛋白质聚集和肌肉病理肌原纤维肌病由于突变的MFM引起的基因。作为一种新的方法，我们将使用多色共聚焦单粒子光谱方法，如扫描强荧光靶点（SIFT）来分析结蛋白突变体和其他MFM相关蛋白的蛋白质聚集体，这些蛋白质聚集体先前已通过转染和体外组装研究进行了表征。重点将是病理性蛋白质聚集体的形成，分子结构，以及同源以及heteroloxyprotein-protein在活细胞中的相互作用，并在单分子水平的表征。通过测试直接靶向病理性蛋白质寡聚体、等位基因特异性敲低、热休克蛋白诱导剂和影响自噬和蛋白酶体代谢的聚集体清除的化合物的新型化合物来解决治疗前景。