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（由申请人提供）：淀粉样蛋白疾病是一组高度多样化的退行性疾病，以跨β片聚集体或淀粉样原纤维命名，它们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病、帕金森病、肌萎缩侧索硬化症。特定疾病中的硬化症以及全身性转甲状腺素蛋白和轻链淀粉样原纤维通常包含一种特定的疾病。 30 多种不同蛋白质中的一种的聚集与一系列病理学相关，这些蛋白质在个体的一生中都会表达，但仅在老年时才会错误折叠、聚集和积累。受影响组织中的淀粉样变性导致了“淀粉样蛋白假说”的形成，即蛋白质聚集过程通过毒性功能获得机制导致组织变性，然而，蛋白质之间的机制联系。淀粉样蛋白结构可以在受影响的个体中大量存在而不会引起症状，但目前尚不清楚。因此，主要但仍备受争议的假设认为，错误折叠蛋白的小可溶性寡聚体聚集是导致这种情况的原因。拟议项目的目的是通过研究从甲状腺素运载蛋白淀粉样变性患者中分离出的寡聚物来仔细检查寡聚物毒性假设并深入了解寡聚物毒性机制。这是唯一一种监管机构批准使用抗淀粉样蛋白生成药物来阻止疾病进展的淀粉样蛋白疾病，因此可以从症状前和有症状的患者以及接受抗淀粉样蛋白生成治疗的患者中重复获取血液样本。免疫分离和表征患者来源的转甲状腺素蛋白寡聚体，并使用转录组学和蛋白质组学破译原代组织培养物中激活的细胞毒性途径（K99）。体内，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，即阿尔茨海默病和帕金森病，并评估干扰所公开途径的治疗潜力（R00），预计结果将产生重要的积极影响。因为它们全面描述了寡聚蛋白聚集体对组织变性的贡献，并有望指导该领域努力开发有效、有针对性和成功的治疗与年龄相关的淀粉样蛋白疾病的疗法。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions.

α-突触核蛋白病转基因小鼠模型中突出的小胶质细胞内含物与神经元病变不同。

DOI：
发表时间：
2020
期刊：
影响因子：
7.1
作者：
Tanriöver, Gaye;Bacioglu, Mehtap;Schweighauser, Manuel;Mahler, Jasmin;Wegenast;Skodras, Angelos;Obermüller, Ulrike;Barth, Melanie;Kronenberg;Nilsson, K Peter R;Shimshek, Derya R;Kahle, Philipp J;Eisele, Yvonn
通讯作者：
Eisele, Yvonn

Molecular Imaging of Cardiac Amyloidosis.

心脏淀粉样变性的分子影像。