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Advancing Our Understanding of Oligomer Toxicity in Age-Related Amyloid Disorders

增进我们对年龄相关淀粉样蛋白疾病中寡聚物毒性的理解

基本信息

批准号：
10092052
负责人：
Yvonne Simone Eisele
金额：
$ 24.9万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092052
关键词：
Acute Affect Age Alzheimer&apos s Disease Amyloid Amyloid Fibrils Amyloid beta-Protein Amyloid fibers Amyloidosis Amyotrophic Lateral Sclerosis Animal Model Biochemical Biophysics Blood specimen Cardiac Cardiomyopathies Cells Characteristics Clinical Cryoelectron Microscopy Data Degenerative Disorder Disease Disease Progression Drops Epitopes Formulation Goals Human Hydrophobicity In Vitro Individual Knowledge Lead Link Longitudinal Studies Memory Loss Mitotic Movement Disorders Names Neurons Outcome Parkinson Disease Pathogenicity Pathologic Pathology Pathway interactions Patients Peripheral Nervous System Diseases Pharmaceutical Preparations Physiological Plasma Prealbumin Process Proteins Proteome Proteomics Research Rodent Model Sampling Stable Populations Structure Symptoms Techniques Testing Therapeutic Time Tissue Sample Tissues Toxic effect Transgenic Animals age related age related neurodegeneration alpha synuclein amyloid structure base beta pleated sheet biophysical properties cell type clinical phenotype cytotoxicity design extracellular gain of function in vivo in vivo evaluation insight misfolded protein novel novel therapeutic intervention prevent primary amyloidosis of light chain type protein aggregation protein misfolding public health relevance resilience response tissue culture tissue degeneration tool transcriptome transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Amyloid diseases are a group of highly diverse degenerative disorders, named after the cross-ß-sheet aggregates or amyloid fibrils that are the histopathological hallmarks of these maladies. Prominent examples include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, as well as the systemic transthyretin and light chain amyloidoses. Amyloid fibrils in a given disease generally comprise one specific protein. Aggregation of one of more than 30 different proteins is linked to a spectrum of pathologies. Typically, these proteins are expressed throughout the lifetime of an individual, but misfold, aggregate and accumulate only at an older age. The invariant presence of amyloid structures in affected tissue has led to the formulation of the "amyloid hypothesis", i.e., the idea that the process of protein aggregation causes tissue degeneration by a toxic gain-of-function mechanism. However, the mechanistic connection between protein aggregation and tissue degeneration is not understood yet. Amyloid structures can be present in fairly large quantities in affected individuals without causing symptoms. Therefore, the leading, but still highly controversial hypothesis postulates that small, soluble oligomeric aggregates of the misfolded proteins are drivers of the toxicity cascade. The objective of the proposed project is to scrutinize the oligomer toxicity hypothesis and to gain insight into the mechanism of oligomer toxicity by studying oligomers isolated from patients with transthyretin amyloidosis. Importantly, this is the only amyloid disease where a regulatory agency approved anti-amyloidogenic drug that halts disease progression is available. It is therefore possible to repeatedly obtain blood samples from presymptomatic and symptomatic patients, as well as from patients undergoing anti-amyloidogenic treatment. I will immunoisolate and characterize patient-derived transthyretin oligomers and decipher the cytotoxicity pathways activated in primary tissue cultures using transcriptomics and proteomics (K99). The next step will then be to probe these findings in vivo, to expand the knowledge gained to the most common age-related neurodegenerative disorders, namely Alzheimer's and Parkinson's diseases, and to evaluate the therapeutic potential of interference with the disclosed pathways (R00). The outcomes are expected to have an important positive impact because they comprehensively delineate the contribution of oligomeric protein aggregates to tissue degeneration and are anticipated to guide the field in its endeavor to develop effective, targeted and successful therapeutics for age-related amyloid disorders.