Probing the biochemical mechanism of amyloid disease

描述（由申请人提供）：我们试图了解人类淀粉样蛋白疾病组织变性特征的分子机制，并利用这一见解开发新的治疗策略和诊断方法来改善人类淀粉样蛋白病。在具体目标1中，我们专注于理解为什么衰老是甲状腺转维蛋白淀粉样变发病的重要危险因素。所有迹象表明，淀粉样蛋白疾病不是由于淀粉样蛋白原纤维在一生中缓慢、渐进式积累引起的。相反，一种与年龄相关的生理变化似乎触发了它们的发作。由于转甲状腺素是由肝脏合成和降解的，而从淀粉样蛋白患者到肝癌患者的肝移植会导致后者快速的淀粉样变，因此我们相信，研究淀粉样变患者的肝脏生理学，以及正常的年轻和老年供体，将为了解该疾病的病因提供重要线索。在特定目标2中，我们利用一流的淀粉样蛋白生成抑制剂在两个安慰剂对照的人类临床试验中测试淀粉样蛋白假说。我们还将分离特定的聚集体形态，阻止这些中间体进一步组装并评估它们的毒性。此外，将开发新技术来表征氧化代谢物池背景下的淀粉样蛋白沉积，这可能有助于这些疾病。在具体目标3中，我们将继续开发新的治疗策略，以发现分泌调节剂为中心，这些化合物使细胞不允许分泌高度不稳定的淀粉样蛋白。不像在上一个资助期发现的转甲状腺素疾病特异性天然状态动力学稳定剂，这些化合物应该对治疗许多淀粉样蛋白疾病有用。最后，我们寻求发展正电子发射断层扫描（PET）诊断，对活体淀粉样蛋白疾病中最早出现的聚集体进行成像，以便在实质性组织变性发生之前开始治疗。

DESCRIPTION (provided by applicant): We seek to understand the molecular mechanism underlying the tissue degeneration characteristic of human amyloid diseases and to use this insight to develop new therapeutic strategies and diagnostics to ameliorate the human amyloidoses. In specific aim 1, we focus on understanding why aging is such an important risk factor for the onset of the transthyretin amyloidoses. All indications are that amyloid diseases do not result from slow, progressive accumulation of amyloid fibrils over a lifespan. Instead, an aging-related physiological change appears to trigger their onset. Since transthyretin is synthesized and degraded by the liver, and since liver transplantation from an amyloid patient into a liver cancer patient initiates rapid amyloidosis in the latter, we are confident that studying liver physiology in amyloidosis, and normal young and old donors will reveal important clues about the etiology of this disease. In specific aim 2, we utilize first-in-class amyloidogenesis inhibitors to test the amyloid hypothesis in two placebo-controlled human clinical trials. We will also fractionate specific aggregate morphologies, arrest these intermediates from further assembly and assess their toxicity. Additionally, new technology will be developed to characterize amyloid deposits in the context of the oxidative-metabolite pool, which could contribute to these maladies. In specific aim 3, we will continue to develop new therapeutic strategies centered around the discovery of secretion modulators, compounds that make cells less permissive to the secretion of highly destabilized amyloidogenic proteins. Unlike the transthyretin-disease specific native state kinetic stabilizers discovered in the last funding period, these compounds should be useful in treating numerous amyloid diseases. Lastly, we seek to develop positron emission tomography (PET) diagnostics to image the earliest aggregates appearing in amyloid diseases in living subjects to enable treatment to begin before substantial tissue degeneration occurs.