Aging and the Tissue Response to Misfolded Proteins

衰老和组织对错误折叠蛋白质的反应

• 批准号: 7586153
• 负责人: Joel N Buxbaum
• 金额: $ 38.85万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586153
• 关键词: Affect; Age; Age of Onset; Aging; Alzheimer' s Disease; Amyloidosis; Animals; Apoptosis; Blood Circulation; Cardiac; Cells; Dependence; Deposition; Detection; Development; Disease; Event; Frequencies; Gender; Genes; Genetic Crosses; Genetic Transcription; Genomics; Heart; Hepatocyte; Human; Immune response; In Vitro; Inflammation; Kidney; Kinetics; Label; Liver; Measures; Molecular; Molecular Chaperones; Mutation; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Organ; Organism; Oxidants; Pattern; Phenotype; Play; Prealbumin; Process; Protein Conformation; Protein Precursors; Proteins; Proteomics; Radioactive; Relative (related person); Role; SOD2 gene; Series; Techniques; Tissues; Transgenic Animals; Transgenic Model; animal tissue; base; islet amyloid polypeptide; oxidant stress; protein misfolding; response

DESCRIPTION (provided by applicant): Disorders of protein conformation of wild type proteins increase in frequency with aging. Alzheimers Disease, type II diabetes and senile systemic amyloidosis are the result of tissue deposition of the wild type protein precursors A2, islet amyloid polypeptide and transthyretin, respectively. In the case of A2 and the islet amyloid polypeptide, aggregation and deposition take occur in proximity to the cells producing the precursor proteins. In senile systemic amyloidosis, transthyretin is synthesized in the liver but deposits in the heart, gut and carpal tunnel, never the liver. Biophysical analyses of the processes of aggregation and fibril formation in vitro show similar kinetics for all three proteins, although transthyretin aggregation differs from the others in that it cannot be seeded. We have produced a transgenic model of senile systemic amyloidosis that resembles human senile systemic amyloidosis in terms of its target tissues (heart, gut, kidneys, but not liver), age of onset (from over one year to 2.5 years, and tissue deposition (non-fibrillar and fibrillar). In our analysis of the tissues of these animals, we have found that animals with significant cardiac deposition have a significantly different transcription pattern in both liver and heart than age and gender matched transgenic animals that do not display significant cardiac transthyretin deposition. We have hypothesized that the transcriptional response of the liver to presumably misfolded transthyretin plays a role in tissue deposition at a distance, i.e. in the heart. If the response is not qualitatively or quantitatively sufficient, partially misfolded transthyretin is released from the hepatocyte into the circulation and is free to aggregate and deposit in the heart and kidneys. We will use genomic and proteomic analyses and genetic crosses to investigate the molecular events in the liver, the state of circulating transthyretin, transcription patterns in the target tissues in the transgenic animals and how these vary with aging, genetically induced reduced responsiveness to oxidant stress, genetically determined chaperone deficiency, and a genetic defect in the innate immune response. At the completion of these studies, we should have a more complete understanding of the way in which intact higher organisms respond to potentially pathogenic misfolded proteins and how these processes are affected in aging.

描述（由申请人提供）：野生型蛋白质的蛋白质构象紊乱的频率随着衰老而增加。阿尔茨海默病、II型糖尿病和老年系统性淀粉样变性分别是野生型蛋白前体A2、胰岛淀粉样多肽和运甲状腺素蛋白组织沉积的结果。就A2和胰岛淀粉样蛋白多肽而言，聚集和沉积发生在产生前体蛋白的细胞附近。在老年系统性淀粉样变性中，运甲状腺素蛋白在肝脏中合成，但沉积在心脏、肠道和腕管中，而不是肝脏中。对体外聚集和原纤维形成过程的生物物理分析显示，所有三种蛋白质的动力学相似，尽管运甲状腺素蛋白聚集与其他聚集不同，因为它不能接种。我们建立了老年系统性淀粉样变性的转基因模型，其靶组织（心脏、肠道、肾脏，但不是肝脏）、发病年龄（1岁以上至2.5岁）以及组织沉积（非纤维状和纤维状）与人类老年系统性淀粉样变性相似。在对这些动物的组织进行分析时，我们发现具有显着心脏沉积的动物具有显着不同的转录模式 在肝脏和心脏中，与年龄和性别匹配的转基因动物相比，未表现出显着的心脏运甲状腺素蛋白沉积。我们假设肝脏对可能错误折叠的转甲状腺素蛋白的转录反应在远处（即心脏）的组织沉积中发挥作用。如果反应在质量或数量上不够充分，部分错误折叠的转甲状腺素蛋白就会从肝细胞释放到 循环并自由聚集并沉积在心脏和肾脏中。我们将利用基因组和蛋白质组分析以及遗传杂交来研究肝脏中的分子事件、循环运甲状腺素蛋白的状态、转基因动物靶组织中的转录模式以及它们如何随衰老而变化、遗传诱导的氧化应激反应性降低、遗传决定的伴侣缺陷和遗传缺陷 在先天免疫反应中。在完成这些研究后，我们应该更全面地了解完整的高等生物体对潜在致病性错误折叠蛋白质的反应方式以及这些过程在衰老过程中如何受到影响。