Cross-seeding of Protein Misfolding as a Disease Mechanism

蛋白质错误折叠作为疾病机制的交叉播种

• 批准号: 8299342
• 负责人: CLAUDIO SOTO
• 金额: $ 34.45万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299342
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Animal Model; Animals; Biological; Biological Assay; Blood; Blood Transfusion; Brain; Breeding; Cell physiology; Chronic; Clinical; Data; Deposition; Disease; Endoplasmic Reticulum Degradation Pathway; Epidemiologic Studies; Etiology; Event; Exhibits; Exposure to; Functional disorder; Goals; Impairment; In Vitro; Infection; Mediating; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Organ; Parkinson Disease; Pathologic Processes; Pathology; Pathway interactions; Patients; PrPSc Proteins; Preventive Intervention; Prion Diseases; Prions; Process; Proteins; Publishing; Research; Risk Factors; Route; Severities; Structure; Study Subject; Symptoms; System; Technology; Testing; Tissues; Transgenic Mice; base; design; diabetes risk; disorder prevention; human disease; in vivo; information gathering; islet amyloid polypeptide; mouse model; novel; protein aggregate; protein aggregation; protein misfolding; protein protein interaction; research study; response; transmission process

DESCRIPTION (provided by applicant): Protein Misfolding Disorders (PMDs) include several diverse diseases such as Alzheimer's disease (AD), Parkinson's disease, transmissible spongiform encephalopathies (TSEs, also known as prion disorders) and type 2 diabetes (T2D), among many others. The central event in these diseases is the accumulation of a misfolded form of a naturally expressed protein, which becomes toxic and induces tissue damage, organ dysfunction and disease. Despite the diversity of clinical symptoms associated to different PMDs, many similarities in their mechanism suggest that distinct pathologies may cross-talk at the molecular level to enhance each other. This proposal is structured around the hypothesis that misfolded proteins associated to one PMD might initiate or accelerate the pathogenic cascade of a second PMD-related disease through a cross-seeding mechanism. We plan to study this subject in a comprehensive way using various animal models and novel in vitro technologies developed in our lab. The studies will focus on 3 diseases of the PMD group: AD, T2D and TSEs. We have recently described the pathological interaction between misfolded prions (PrPSc) and amyloid-¿ (A¿), the proteins implicated in TSEs and AD, respectively. Our results showed that both diseases were dramatically accelerated when the two misfolded proteins were present simultaneously in the brain. The information gathered from these studies encouraged us to pursue further this line of research, and expand it to assess the putative interaction between the two most prevalent PMDs: AD and T2D. The main goal of this project is to evaluate the molecular cross-talk between misfolded proteins as a pathogenic mechanism implicated in the initiation of these diseases. Experiments are designed to provide proof-of-concept data in animal models for a pathogenic interaction among these diseases and various in vitro studies to investigate if cross- seeding of protein misfolding may explain in part the disease interaction. We will also study whether the disease can be induced or accelerated through a medically relevant route of exposure (blood transfusion) to heterologous misfolded oligomeric aggregates. The findings generated in this project may provide a new paradigm to understand the etiology and molecular basis of highly prevalent and insidious diseases, such as AD, T2D and TSEs and may offer new avenues for developing strategies for disease prevention and intervention. PUBLIC HEALTH RELEVANCE: Some of the most debilitating and chronic human diseases involve the misfolding, aggregation and tissue accumulation of proteins. These protein misfolding diseases (PMDs) include highly prevalent diseases, such as type 2 diabetes and Alzheimer's disease. One of the most important unanswered questions regarding PMDs is to understand the factors and mechanisms involved in the initiation of the pathology. The overarching hypothesis of this project is that misfolded proteins associated to one PMD might initiate or accelerate the pathogenic cascade of a second PMD-related disease through a cross-seeding mechanism. This hypothesis will be comprehensible tested using various in vivo and in vitro studies in models of Alzheimer's disease, type 2 diabetes and prion diseases. The results obtained in this study may open a new view to understand the origin of some of the most noxious forms of PMDs.

描述（由申请人提供）：蛋白质错误折叠障碍（PMDs）包括几种不同的疾病，如阿尔茨海默病（AD），帕金森病，传染性海绵状脑病（tse，也称为朊病毒疾病）和2型糖尿病（T2D）等。这些疾病的中心事件是自然表达的蛋白质的错误折叠形式的积累，它变得有毒并诱导组织损伤，器官功能障碍和疾病。尽管与不同pmd相关的临床症状多种多样，但其机制上的许多相似性表明，不同的病理可能在分子水平上相互交流以增强彼此。这一建议是基于一个假设，即与一种PMD相关的错误折叠蛋白可能通过交叉播种机制启动或加速另一种PMD相关疾病的致病级联。我们计划利用我们实验室开发的各种动物模型和新的体外技术对这一课题进行综合研究。研究将集中在PMD组的3种疾病：AD、T2D和tse。我们最近描述了错误折叠的朊病毒（PrPSc）和淀粉样蛋白-¿（A¿）之间的病理相互作用，这两种蛋白分别与tse和AD有关。我们的研究结果表明，当这两种错误折叠的蛋白质同时出现在大脑中时，这两种疾病的发病速度都会大大加快。从这些研究中收集到的信息鼓励我们进一步进行这方面的研究，并将其扩展到评估两种最常见的经前综合症：AD和T2D之间可能的相互作用。该项目的主要目标是评估错误折叠蛋白之间的分子串扰作为一种涉及这些疾病起始的致病机制。实验旨在为这些疾病之间的致病相互作用和各种体外研究提供动物模型的概念验证数据，以调查交叉播种蛋白质错误折叠是否可以部分解释疾病相互作用。我们还将研究这种疾病是否可以通过医学上相关的暴露途径（输血）诱发或加速异源错误折叠的寡聚物聚集体。本项目的研究结果可能为了解AD、T2D和tse等高流行和隐匿性疾病的病因和分子基础提供新的范式，并可能为制定疾病预防和干预策略提供新的途径。