Molecular Basis of Light Chain Amyloidosis

描述(申请人提供)：我们的长期目标是了解蛋白质沉积疾病的详细分子机制和触发淀粉样原纤维形成的因素。由于人口老龄化，蛋白质沉积疾病的发病率越来越高。了解沉积机制将有助于临床治疗的合理设计。在这项建议中，我们关注一系列称为轻链沉积疾病的疾病，特别是AL或轻链淀粉样变性，有时也称为原发性淀粉样变性，这是最常见的系统性淀粉样变性。这些疾病涉及免疫球蛋白轻链的可变区VL的沉积。我们将继续研究一对密切相关的VLS的性质，一个是淀粉样变性(SMA)，另一个是良性的(LEN)。目的一是阐明轻链聚集的详细分子机制，特别是关于中间体的表征以及各种因素促进或抑制轻链纤颤的机制。目的2是研究表面，特别是膜在轻链纤颤中的作用。根据初步结果，我们假设表面在纤颤的发生中起着非常重要的作用。目的3是研究氧化和氧化应激对轻链可变区纤颤的影响。氧化应激被认为是许多蛋白质沉积疾病的重要病因。目标4是寻找轻链聚集和纤维形成的抑制剂。我们假设适当的多肽将通过几种可能的机制起到抑制聚集的作用。我们将筛选组合多肽文库和轻链中的多肽片段，以及一些低分子量化合物作为VL纤颤的潜在抑制剂。

DESCRIPTION (provided by applicant): Our long-term goal is to understand the detailed molecular mechanisms of protein deposition diseases and the factors that trigger amyloid fibril formation. Protein deposition diseases are of increasing prevalence, due to the aging of the population. Understanding the mechanisms of deposition will facilitate the rational design of clinical therapies. In this proposal, we focus on a constellation of diseases known as light chain deposition diseases, in particular on AL or light chain amytoidosis, sometimes also known as primary amyloidosis, which is the most common systemic amyloidosis. These diseases involve the deposition of the variable domain of the immunoglobulin light chain, VL. We will continue our studies on the properties of a pair of closely related VLs, one amyloidogenic (SMA), the other benign (LEN). Aim 1 is to elucidate the detailed molecular mechanism of light chain aggregation, especially with respect to characterizing intermediates and the mechanisms by which various factors accelerate or inhibit light chain fibrillation. Aim 2 is to investigate the role of surfaces, especially membranes, in light chain fibrillation. Based on preliminary results, we hypothesize that surfaces play a very important role in the initiation of fibrillation. Aim 3 is to investigate the rote of oxidation and oxidative stress on the fibrillation of light chain variable domains. Oxidative stress is thought to be an important factor in the etiology of many protein deposition diseases. Aim 4 is to find inhibitors of light chain aggregation and fibril formation. We hypothesize that appropriate peptides will act as inhibitors of aggregation through several possible mechanisms. We will screen both a combinatorial peptide library and peptide fragments from light chains as well as some low MW compounds for potential inhibitors of VL fibrillation.