Aging and the Tissue Response to Misfolded Proteins

描述(申请人提供)：野生型蛋白的蛋白质构象紊乱随着年龄的增长而增加。阿尔茨海默病、II型糖尿病和老年性系统性淀粉样变性分别是野生型蛋白前体A2、胰岛淀粉样多肽和转甲状腺蛋白组织沉积的结果。在A2和胰岛淀粉样多肽的情况下，聚集和沉积发生在产生前体蛋白的细胞附近。在老年性系统性淀粉样变性中，转甲状腺素在肝脏合成，但沉积在心脏、肠道和腕管，而不是肝脏。对体外聚集和纤维形成过程的生物物理分析表明，这三种蛋白质的动力学相似，尽管转甲状腺蛋白聚集不同于其他蛋白质，因为它不能被种子。我们已经建立了一种老年性系统性淀粉样变性的转基因模型，该模型在靶组织(心脏、肠道、肾脏，但不包括肝脏)、发病年龄(从一年多到2.5岁)和组织沉积(非纤维和纤维)方面类似于人类老年性系统性淀粉样变性。在我们对这些动物组织的分析中，我们发现心脏显著沉积的动物在肝脏和心脏中的转录模式与年龄和性别匹配的转基因动物显著不同，这些转基因动物没有表现出明显的心脏转甲状腺素沉积。我们假设，肝脏对错误折叠的转甲状腺素的转录反应在远处的组织沉积中发挥作用，即在心脏。如果反应不是定性或定量充分的，部分错误折叠的反式甲状腺激素会从肝细胞释放到循环中，并自由聚集和沉积在心脏和肾脏中。我们将使用基因组和蛋白质组分析以及遗传杂交来研究转基因动物肝脏中的分子事件、循环中的转甲状腺素状态、靶组织中的转录模式以及这些模式如何随年龄变化、遗传导致的氧化应激反应降低、遗传决定的伴侣蛋白缺乏以及先天免疫反应中的遗传缺陷。在这些研究完成后，我们应该更全面地了解完整的高等生物对潜在致病的错误折叠蛋白质的反应方式，以及这些过程在衰老过程中是如何受到影响的。

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.