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: 8641401
• 负责人: CLAUDIO SOTO
• 金额: $ 33.3万
• 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/8641401
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid Protein AA; 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（由适用提供）：蛋白质错误折叠式疾病（PMD）包括几种潜水疾病，例如阿尔茨海默氏病（AD），帕金森氏病，可传染性的赞助型脑病（TSE，也称为Prion疾病）和其他许多其他疾病。这些疾病中的中心事件是一种自然表达的蛋白质错误折叠形式的积累，该蛋白会成为毒性和诱发的组织损伤，器官功能障碍和疾病。尽管与不同PMD相关的临床症状多样，但其机制的许多相似性表明，不同的病理可能会在分子水平上跨性别，从而相互增强。该提议围绕以下假设：与一个​​PMD相关的杂物蛋白可能会通过交叉种子机制引发或加速第二种PMD相关疾病的致病性级联反应。我们计划使用各种动物模型和我们实验室中开发的新型体外技术以一种全面的方式研究这一主题。这些研究将重点放在PMD组的3种疾病上：AD，T2D和TSE。我们最近描述了错误折叠的prions（PRPSC）和淀粉样蛋白（A a）的病理相互作用，分别在TSE和AD中实现的蛋白质。我们的结果表明，当两种折叠的蛋白质在大脑中呈现时，两种疾病都大大加速了。从这些研究中收集的信息鼓励我们进一步进行这项研究，并将其扩展以评估两个最普遍的PMD之间的推定相互作用：AD和T2D。该项目的主要目标是评估错误折叠蛋白的分子串扰，作为在这些疾病启动中实施的一种致病机制。实验旨在在动物模型中提供概念验证数据，以在这些疾病和各种体外研究之间发生致病性相互作用，以研究蛋白质折叠的交叉种子是否可能部分解释疾病相互作用。我们还将研究该疾病是否可以通过医学上相关的暴露途径（输血）诱导或加速疾病，以异源错误折叠的寡聚聚集体。该项目中产生的发现可能会提供一个新的范式，以了解高度普遍和阴险疾病的病因和分子基础，例如AD，T2D和TSE，并可能为制定预防疾病和干预策略提供新的途径。