Protein therapeutics inspired by importins

项目摘要 蛋白质聚集是几种神经退行性疾病的基础，并且是神经退行性疾病的病理标志。 肌萎缩侧索硬化症（ALS）。在这种毁灭性的疾病中，细胞质内含物 在退化的运动神经元中发现了聚集的、通常是高度后修饰的蛋白质， 周围的少突胶质细胞没有特定的药物治疗来防止蛋白质聚集 或促进分解和清除现有的聚集体， 神经变性这一探索性的R21建议建立在最近发现的基础上，即核输入因素 importin β-超家族的成员可以对其他蛋白质发挥解聚酶活性。强大功能整合到 蛋白质生物化学和结构生物学与我们在核质运输的专业知识，我们寻求学习 从引入解聚酶活性的生物学原理，并利用这些知识来设计更多的 多功能蛋白质疗法我们认为，高风险、高回报的R21融资机制将推动 创造性和勤奋的追求，以解决困难的生物学问题，使我们的研究计划， 在开发新型蛋白质治疗剂方面取得重大进展， 聚合来

Project Summary Protein aggregation underlies several neurodegenerative diseases and is a pathological hallmark of Amyotrophic Lateral Sclerosis (ALS). In this devastating disease, cytoplasmic inclusions containing aggregated, often hyper post-translationally modified proteins are found in degenerating motor neurons and surrounding oligodendrocytes. There is no specific pharmacological treatment to prevent protein aggregation or promote disaggregation and clearance of existing aggregates that drive the progression of neurodegeneration. This exploratory R21 proposal builds upon the recent discovery that nuclear import factors of the importin β-superfamily can exert disaggregase activity toward other proteins. Combining the power of protein biochemistry and structural biology with our know-how in nucleocytoplasmic transport, we seek to learn from importins the biological principles for disaggregase activity and use this knowledge to design more versatile protein therapeutics. We believe that the high-risk, high-reward R21 funding mechanism will fuel the creative and diligent pursuit of answers to difficult biological questions, permitting our research program to achieve significant advancements in developing novel protein therapeutics that reduce pathogenic protein aggregation.