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，也是 肌萎缩侧索硬化症(ALS)。在这种毁灭性的疾病中，细胞质内含物含有 在退化的运动神经元中发现聚集的、通常是超翻译后修饰的蛋白质 周围的少突胶质细胞。没有特殊的药物治疗来防止蛋白质聚集。 或促进现有集合体的分解和清除，从而推动 神经退行性变。这一探索性的R21提议建立在最近的发现之上，即核进口因素 Importin的β-超家族成员可以对其他蛋白质发挥解聚活性。结合了 蛋白质生物化学和结构生物学利用我们在核质运输方面的诀窍，我们寻求学习 了解解聚酶活性的生物学原理，并利用这些知识设计出更多 多种多样的蛋白质疗法。我们相信，高风险、高回报的R21融资机制将推动 创造性和勤奋地寻求疑难生物学问题的答案，使我们的研究计划能够 在开发降低致病蛋白的新型蛋白质疗法方面取得重大进展 聚合。

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.