Biochemical and structural studies of amyloid enhancing factor

系统性AA淀粉样变性是一种影响人类、哺乳动物和鸟类的蛋白质错误折叠疾病。该疾病是由AA淀粉样纤维在脾、肾和肝中的形成和沉积引起的。虽然AA淀粉样蛋白原纤维由血清淀粉样蛋白A（SAA）1.1蛋白的片段组成，但长期以来有证据表明，将称为淀粉样蛋白增强因子（AEF）的粗制脾提取物注射到适当的受体中会加速淀粉样蛋白沉积。由于发现这些部分富集的脾提取物通常包含至少小水平的AA原纤维，因此建议了朊病毒样繁殖机制，尽管活性物质从未被完全纯化。利用现代生物化学方法和SAA纤维形成的细胞模型，我们将AEF从其天然来源中分离出来，用一系列生物物理方法分析其分子特性。由此产生的假设有关的宪法和构象组成，然后可以测试在体外重建。由于传播是一般构象疾病的一个重要特征，预期的数据可能具有广泛的科学和公共利益。

Systemic AA amyloidosis is a protein misfolding disease that affects humans, mammals and birds. The disease is caused by the formation and deposition of AA amyloid fibrils in spleen, kidneys and liver. While AA amyloid fibrils are composed of fragments of the serum amyloid A (SAA) 1.1 protein, there is long-standing evidence that injection of crude spleen extracts, termed amyloid enhancing factor (AEF), into appropriate recipients accelerates amyloid deposition. As these partially enriched spleen extracts were found to often comprise at least small levels of AA fibrils, a prion-like mechanism of propagation was suggested, although the active species was never fully purified. Using modern biochemical methods and a cell model of SAA fibril formation we will isolate AEF from its native source to analyze its molecular properties with a battery of biophysical methodologies. Resulting hypotheses concerning the constitutional and conformational composition can then the tested by in vitro reconstitution. As spreading is an important feature of conformational diseases in general, expected data could be of broad scientific and public interest.