Probing the biochemical mechanism of amyloid disease

探究淀粉样蛋白病的生化机制

• 批准号: 7145577
• 负责人: JEFFERY W KELLY
• 金额: $ 61.99万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145577
• 关键词: aging; albumins; amyloidosis; chemical aggregate; clinical research; clinical trials; diagnosis design /evaluation; human subject; human therapy evaluation; laboratory rat; liquid chromatography mass spectrometry; metabolism disorder chemotherapy; molecular pathology; patient oriented research; pharmacokinetics; positron emission tomography; protein biosynthesis; secretion

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.

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，以改善人类淀粉样蛋白病。在具体目标1中，我们重点了解为什么衰老是甲状腺素运载蛋白淀粉样变性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纤维在整个生命周期中缓慢、渐进的积累而引起的。相反，与衰老相关的生理变化似乎触发了它们的发作。由于甲状腺素运载蛋白是由肝脏合成和降解的，并且由于淀粉样蛋白患者的肝移植到肝癌患者中会引发后者的快速淀粉样变性，因此我们相信，研究淀粉样变性中的肝脏生理学，以及正常的年轻和老年供体将揭示关于这种疾病病因的重要线索。在具体目标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体临床试验中测试淀粉样蛋白假说。我们还将压裂特定的聚集体形态，逮捕这些中间体进一步组装和评估其毒性。此外，将开发新技术来表征氧化代谢物库中的淀粉样蛋白沉积物，这可能会导致这些疾病。在具体目标3中，我们将继续开发新的治疗策略，这些策略围绕着发现分泌调节剂，即使细胞不太允许高度不稳定的淀粉样蛋白分泌的化合物。与上一个资助期发现的甲状腺素运载蛋白疾病特异性天然状态动力学稳定剂不同，这些化合物应该可用于治疗多种淀粉样蛋白疾病。最后，我们寻求开发正电子发射断层扫描（PET）诊断，以对活体中淀粉样蛋白疾病中出现的最早聚集体进行成像，以使治疗能够在实质性组织变性发生之前开始。