Immunoglobulin Light Chain Fibrillogenesis

AL淀粉样变性是一种骨髓浆细胞病变，与多发性骨髓瘤和其他单克隆伽玛病有关，其中突变的免疫球蛋白轻链过度表达并沉积在许多器官中。它是美国最常见的系统性淀粉样变性，估计每年发生超过5-12人/百万人。淀粉样蛋白研究和治疗项目在波士顿大学有很强的研究记录，并在国际上作为患者治疗的转诊中心。我们率先采用静脉注射美法兰和自体干细胞治疗AL淀粉样变性，取得了令人鼓舞的效果，但只有不到一半的患者有资格接受这种治疗。如果没有有效的治疗，中位生存期很差，因为淀粉样蛋白沉积会导致进行性器官衰竭，中位生存期为110-18个月。本项目的总体假设是，轻链基因的突变引起蛋白质修饰，这些修饰与宿主组织环境相互作用，导致纤维形成。本项目的目标是：确定导致纤维形成的淀粉样轻链的遗传和结构特征；确定促进淀粉样蛋白沉积和器官衰竭的宿主组织的反应；建立AL淀粉样变动物模型；并将其用于免疫疗法的临床前测试。为了达到这些目标，我们将检查在我们的大量AL淀粉样变性患者转诊人群中发现的淀粉样轻链的表达基因序列和种系起源（项目1）。我们将描述淀粉样蛋白轻链蛋白聚合的生物物理性质和结构构象（项目2）。我们将分析淀粉样蛋白轻链蛋白本身，它们的翻译后修饰，以及它们相互作用的分子和组织反应（项目3）。使用计算机建模，我们将预测模型中的纤维原氨基酸，并在体外和动物模型中进行测试（项目1-3）。将在动物模型中开发和测试基于免疫疗法的新治疗方法（项目1和项目4）。一个复杂的蛋白质生物化学和免疫病理学核心和最先进的质谱核心为该计划提供必要的支持。这些研究将对我们的患者和其他形式的淀粉样变（包括阿尔茨海默病）患者都有潜在的益处。

AL amyloidosis is a bone marrow plasma cell dyscrasia, related to multiple myeloma and other monoclonal gammopathies, in which a mutant immunoglobulin light-chain is over-expressed and deposits in many organs. It is the most common form of systemic amyloidosis in the Unite States, estimated to occur in more than 5-12 persons/million/year. The Amyloid Research and Treatment Programs at Boston University has a strong record of research and is internationally as a referral center for patient treatment. We have pioneered aggressive treatment using intravenous melphalan and autologous stem cell rescue with promising results for AL amyloidosis, however less than half of the patients are eligible for such treatment. Without effective therapy, the median survival is poor, as amyloid deposition leads to progressive organ failure and death within a median of 110-18 months. The overall hypothesis of this Program Project Grant is that mutations in light chain genes give rise to protein modifications that interact with the host tissue environment that cause fibrillogenesis. The goals of this Program Project are to: identify the genetic and structural features of amyloidogenic light chains that lead to fibril formation; determine the responses of host tissues that promote amyloid deposition and organ failure; develop an animal model of AL amyloidosis; and exploit it for preclinical testing of immunotherapy. To reach these goals we will examine the expressed gene sequence and germline origin of amyloidogenic light chains found in our large referral population of patients with AL amyloidosis (Project 1). We will characterize the biophysical properties and structural conformation responsible for polymerization of the amyloid light chain protein (Project 2). We will analyze the amyloidogenic light chain protein themselves, their post- translational modifications, and their interacting molecules and tissue responses (Project 3). Using computer modeling we will predict fibrillogenic amino acids in models and test these in vitro and in an animal model (Projects 1-3). Novel approaches to treated based on immunotherapy will be developed and tested in the animal model (Projects 1 and 4). A sophisticated protein biochemistry and immunopathology core and a state-of-the-art mass spectrometry core provide essential support to the Program. These investigations will potentially benefit both our patients and those with other forms of amyloidosis including Alzheimer's disease.