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: 8450044
• 负责人: CLAUDIO SOTO
• 金额: $ 33.99万
• 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/8450044
• 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.

描述（由申请人提供）：蛋白质错误折叠疾病（PMD）包括几种不同的疾病，例如阿尔茨海默病（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（T2 D）等。这些疾病的中心事件是天然表达蛋白质的错误折叠形式的积累，其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相关的临床症状的多样性，但其机制的许多相似性表明，不同的病理可能在分子水平上相互干扰以增强彼此。这个建议是围绕这样的假设，即与一个PMD相关的错误折叠蛋白质可能通过交叉播种机制启动或加速第二个PMD相关疾病的致病级联反应。我们计划使用我们实验室开发的各种动物模型和新型体外技术来全面研究这一主题。这些研究将集中在PMD组的3种疾病：AD、T2 D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，这两种蛋白质分别与TSE和AD有关。我们的研究结果表明，当两种错误折叠的蛋白质同时存在于大脑中时，这两种疾病都会急剧加速。从这些研究中收集的信息鼓励我们进一步开展这一研究，并将其扩展到评估两种最常见的PMD之间的假定相互作用：AD和T2 D。该项目的主要目标是评估错误折叠蛋白质之间的分子串扰作为这些疾病发生的致病机制。设计实验以在动物模型中为这些疾病之间的致病性相互作用提供概念验证数据，并进行各种体外研究以研究蛋白质错误折叠的交叉播种是否可以部分解释疾病相互作用。我们还将研究是否可以通过暴露于异源错误折叠的寡聚体的医学相关途径（输血）诱导或加速疾病。该项目中产生的发现可能提供一种新的范式，以了解高度流行和隐匿性疾病（如AD，T2 D和TSE）的病因学和分子基础，并可能为制定疾病预防和干预策略提供新的途径。