Molecular Basis of Light Chain Amyloidosis

描述（由申请人提供）：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纤维形成的因素。由于人口老龄化，蛋白质沉积疾病的患病率越来越高。了解沉积机制将有助于临床治疗的合理设计。在这项提案中，我们专注于一系列被称为轻链沉积疾病的疾病，特别是AL或轻链淀粉样变性，有时也被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可变结构域VL的沉积。我们将继续研究一对密切相关的VL的性质，一个是淀粉样蛋白（SMA），另一个是良性的（LEN）。目的1是阐明轻链聚集的详细分子机制，特别是关于表征中间体和各种因素加速或抑制轻链原纤化的机制。目的2是研究表面，特别是膜，在轻链纤维化中的作用。基于初步的结果，我们假设，表面起着非常重要的作用，在启动纤颤。目的3探讨氧化和氧化应激对轻链可变区纤维化的影响。氧化应激被认为是许多蛋白质沉积疾病的病因学中的重要因素。目的4是寻找轻链聚集和纤维形成的抑制剂。我们推测，适当的肽将通过几种可能的机制作为聚集的抑制剂。我们将筛选组合肽库和轻链肽片段以及一些低分子量化合物，以寻找VL纤维化的潜在抑制剂。

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.