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Molecular mechanisms of transthyretin amyloidosis

运甲状腺素蛋白淀粉样变性的分子机制

基本信息

批准号：
10115719
负责人：
PETER Edwin WRIGHT
金额：
$ 45.64万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115719
关键词：
Address Affect Age Aging Amyloid Amyloid Fibrils Amyloidosis Biological Assay Cardiomyopathies Complement DNA Sequence Alteration Data Deposition Dissociation Event Extracellular Protein Familial disease Goals Growth Heart Human Hybrids Impairment Individual Kinetics Lead Link Maps Measures Mediating Methods Molecular Molecular Conformation Molecular Weight Multidimensional NMR Techniques Multinuclear NMR Mutation Neurodegenerative Disorders Onset of illness Pathogenicity Pathway interactions Peptides Peripheral Nerves Physiological Play Population Prealbumin Process Proteins Research Role Seeds Shapes Structure Time Tissues Variant Virulence Factors X-Ray Crystallography age related aggregation pathway amyloid formation amyloidogenesis beta pleated sheet biophysical tools cold temperature cytotoxic design early onset experimental study extracellular globular protein human disease inhibitor/antagonist insight monomer mutant novel polymerization proteostasis shear stress small molecule

项目摘要

Many debilitating human diseases are associated with the extracellular misfolding and aggregation of globular proteins to form fibrillar deposits that are rich in β-sheet. There is considerable evidence that the process is initiated by local unfolding of the native structure to form aggregation-prone amyloidogenic intermediates. Aggregation then proceeds via nucleation-growth or downhill polymerization mechanisms. Despite their key role in amyloidogenesis, influencing the kinetic partitioning between aggregation and refolding pathways, very little is known about the structure of amyloidogenic intermediates because of their strong propensity to aggregate. The goals of the present proposal are to apply state-of-the-art NMR methods to elucidate the fundamental molecular events involved in transthyretin amyloidosis. Transthyretin amyloidosis is associated with numerous neurodegenerative diseases and cardiomyopathies. Misfolding and aggregation of transthyretin leads to fibrous deposits in the peripheral nerves and heart. Deposition of wild type protein is age related, whereas the familial diseases associated with genetic mutations that destabilize the quaternary and/or tertiary structure are early onset. The proposed research will provide novel insights into the fundamental molecular mechanisms by which wild type transthyretin aggregates and by which familial mutations destabilize the native transthyretin tetramer and drive the aggregation cascade. Real-time 19F NMR will be used to map the kinetic aggregation landscape of wild type and pathogenic variant transthyretin, characterize and quantify the population of intermediates that accumulate on the aggregation pathway, and examine mechanisms of inhibition by small molecules and peptides. Multidimensional NMR experiments will be utilized to elucidate the structure and dynamics of an alternate conformational state that promotes tetramer dissociation, and of cytotoxic monomeric and oligomeric intermediates, formed on the aggregation pathway, that promote aggregation and fibril growth. This research will advance our understanding of the underlying molecular events that initiate tetramer dissociation and promote entry into and progression down the aggregation cascade that leads to amyloid formation by both wild type human transthyretin and pathogenic variants.

许多使人衰弱的疾病都与细胞外错误折叠和聚集有关