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.

描述（由适用提供）：淀粉样蛋白疾病是一组高度多样的退化性疾病，以横s--骨聚集体或淀粉样蛋白原纤维的命名，这些疾病是这些疾病的组织病理学标志。突出的例子包括阿尔茨海默氏病，帕金森氏病，肌萎缩性侧索硬化症以及全身经甲状腺素蛋白和轻链淀粉样蛋白。给定疾病中的淀粉样蛋白原纤维通常包括一种特定蛋白质。 30多种不同蛋白质之一的聚集与一系列病理有关。通常，这些蛋白质在一个人的整个生命周期中都表达，但仅在年龄较大的年龄就堆积，聚集和积累。淀粉样结构在受影响的组织中的不变存在导致了“淀粉样假说”的公式，即蛋白质聚集过程会通过有毒功能获得的机制导致组织变性。但是，尚不清楚蛋白质聚集和组织变性之间的机械连接。淀粉样蛋白结构可以在受影响的个体中相当大的情况下出现而不会引起症状。因此，领先但仍有高度争议的假设假设假设错误折叠蛋白的小，可溶性的寡聚聚集体是毒性级联的驱动因素。拟议项目的目的是仔细检查低聚物毒性假说，并通过研究从经硫代蛋白淀粉样变性患者中分离出的低聚物，从而深入了解低聚物毒性的机制。重要的是，这是唯一一种监管机构批准抗淀粉样蛋白生成药物的淀粉样蛋白疾病，可以使用疾病进展。因此，可以从症状和症状患者以及接受抗淀粉样蛋白原治疗的患者中反复获得血液样本。我将通过转录组学和蛋白质组学（K99）在原代组织培养物中激活的患者衍生的转染素寡聚物进行免疫分散并表征患者衍生的经甲状腺素素低聚物并解密细胞毒性途径。然后，下一步将是在体内探测这些发现，将获得的知识扩展到最常见的与年龄相关的神经退行性疾病，即阿尔茨海默氏症和帕金森氏病，并评估与公开途径（R00）干扰的治疗潜力。预计结果将产生重要的积极影响，因为它们全面地描述了寡聚蛋白聚集物对组织变性的贡献，并有望指导该领域的努力，以开发有效，有针对性和成功的年龄相关淀粉样蛋白疾病。