Protein therapeutics inspired by importins

受进口蛋白启发的蛋白质疗法

基本信息

批准号：
10506677
负责人：
Gino Cingolani
金额：
$ 42.9万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10506677
关键词：
ALS patients Affinity Amyotrophic Lateral Sclerosis Antibodies Avidity Binding Biological Biological Assay Biology C-terminal Cell Death Cell Nucleus Cells Complex Cryoelectron Microscopy Cytoplasmic Inclusion Data Disease Disease Progression Engineering Epitopes Eukaryotic Cell Frontotemporal Dementia Funding Mechanisms Glycine Goals Guanosine Triphosphate Phosphohydrolases Importins In Vitro Investigation Karyopherins Knowledge Laboratories Learning Link Maps Molecular Motor Neurons Mutagenesis Mutation National Institute of Neurological Disorders and Stroke Nerve Degeneration Nervous System Physiology Neurodegenerative Disorders Neurons Neurosciences Research Nuclear Import Nuclear Localization Signal Nuclear Pore Complex Nuclear Pore Complex Proteins Nuclear Proteins Oligodendroglia Paper Pathogenicity Pathologic Patients Pharmacological Treatment Phenylalanine Process Protein Biochemistry Protein Engineering Proteins Publishing RNA-Binding Proteins Reporting Research Reverse engineering Role Series Site Site-Directed Mutagenesis Structure Tail Testing Therapeutic antibodies Work base cohesion design flexibility frontotemporal lobar dementia-amyotrophic lateral sclerosis fundamental research high reward high risk improved nervous system disorder novel nucleocytoplasmic transport parathyroid hormone-related protein particle polyclonal antibody prevent programs protein TDP-43 protein aggregation receptor sporadic amyotrophic lateral sclerosis structural biology therapeutic protein yeast prion

项目摘要

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.

项目概要蛋白质聚集是多种神经退行性疾病的基础，也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，细胞质包含物。在退化的运动神经元中发现了聚集的、通常是高度翻译后修饰的蛋白质周围少突胶质细胞没有特定的药物治疗来防止蛋白质聚集。或促进现有聚集体的分解和清除，从而推动这项探索性 R21 提案建立在最近发现核输入因素的基础上。 importin β-超家族的成员可以结合其他蛋白质的力量发挥解聚酶活性。凭借我们在核细胞质运输方面的专业知识，我们寻求学习蛋白质生物化学和结构生物学从导入解聚酶活性的生物学原理并利用这些知识来设计更多我们相信高风险、高回报的 R21 融资机制将推动这一发展。创造性和勤奋地寻求困难的生物学问题的答案，使我们的研究计划能够在开发减少致病蛋白的新型蛋白质疗法方面取得重大进展聚合。