A Mouse Model for the Rare Plasma Cell Disease AL Amyloidosis

项目总结/摘要 该应用程序解决了广泛的挑战领域（15）“转化科学”，和具体的挑战 专题15-OD（ORR）-101，“罕见病预防、早期发现和治疗试点项目”。在这 应用，我们建议开发罕见疾病AL的“第二代”转基因小鼠模型 淀粉样变性AL是一种以浆细胞恶液质为特征的疾病， 骨髓中浆细胞的扩增。它还具有蛋白质折叠紊乱的特征， 该疾病的病理是由血浆产生的免疫球蛋白轻链沉积引起的 组织中的纤维蛋白。这导致器官功能障碍、器官衰竭和死亡。淀粉样变性是 得到国会，劳工部，卫生与公众服务部和教育部的认可， 相关机构拨款法案在2005年，2006年和2007年作为一种罕见的和未充分研究的疾病：“ 委员会鼓励NIH将其研究工作扩展到淀粉样蛋白-一组罕见疾病 以组织中异常折叠的蛋白质沉积为特征。这些疾病往往是致命的， 已知的治愈治疗涉及大剂量静脉化疗，随后进行干细胞置换，或 抢救对许多病人是有效的，但这种方法有风险，不适合许多病人，而且不能治愈。" 2006年，NIH罕见疾病办公室召开了一次系统性淀粉样变性焦点小组研讨会， 概述了“系统性淀粉样变性研究的挑战和机遇”， 淀粉样蛋白（Wright DG等人，淀粉样蛋白14（2）：103-112，2007）。该报告将动物模型描述为“......一 特别是关键的研究资源需求。这种动物模型为研究人员提供了最好的机会， 解决淀粉样蛋白疾病发病机制的基本问题：例如，组织嗜性的基础，疾病 触发条件和遗传修饰剂，以及淀粉样前体蛋白加工的作用， 疾病表达。动物模型对于识别和开发潜在的 治疗学“这项提案旨在解决对AL淀粉样变性更好的动物模型的未满足需求， 在美国公民中最常见的系统性淀粉样变性。它将建立在我们最初的经验， 动物模型，支持P01研究“免疫球蛋白轻链纤维形成”。我们将使用一个 一种新的载体，其导致Myc癌基因以组织特异性和阶段特异性的方式表达， 终末分化的B细胞，导致浆细胞的多克隆扩增，然后是单克隆扩增。通过 改造载体以合成人淀粉样蛋白免疫球蛋白轻链，我们希望 复制人类的AL淀粉样变性。小鼠将被表征并用于研究疾病 发病机制和治疗。为进行这项计划，我们需要另一间实验室的协助 技术人员、博士后研究员和研究生，并将增加现有核心设施的使用， 由动物技术人员和转基因技术专家完成。

PROJECT SUMMARY/ABSTRACT This application addresses the broad Challenge Area (15) "Translational Science", and the Specific Challenge Topic 15-OD(ORDR)-101, "Pilot projects for prevention, early detection and treatment of rare diseases". In this application, we propose to develop a "second generation" transgenic mouse model of the rare disease AL amyloidosis. AL is a disease with features of a plasma cell dyscrasia, and is caused by a low grade clonal expansion of plasma cells in the bone marrow. It also has features of a protein folding disorder, in that the pathology in the disease is caused by deposition of the immunoglobulin light chains produced by the plasma cells as fibrillar proteins in tissues. This leads to organ dysfunction, organ failure, and death. Amyloidosis is recognized by Congress, in the Departments of Labor, Health And Human Services, and Education, and Related Agencies Appropriations Bill in 2005, 2006, and 2007 as a rare and understudied disorder: "The Committee encourages NIH to expand its research efforts into the amyloidoses-a group of rare diseases characterized by abnormally folded protein deposits in tissues. These diseases are often fatal and there is no known cure. Treatment involving large-dose intravenous chemotherapy followed by stem cell replacement or rescue is effective for many patients, but this procedure is risky, unsuitable for many patients, and not a cure." In 2006, the Office of Rare Diseases at NIH convened a Systemic Amyloidosis Focus Group Workshop that outlined the "Challenges and Opportunities for Systemic Amyloidosis Research," published in the journal Amyloid (Wright DG et al., Amyloid 14(2): 103-112, 2007). That report described animal models as "....a particularly critical research resource need. Such animal models offer the best chance for investigators to address fundamental questions of amyloid disease pathogenesis: e.g. the basis for tissue tropism, disease triggering conditions and genetic modifiers, as well as the role of amyloid precursor protein processing in disease expression. Animal models are also critical for the identification and development of potential therapeutics." This proposal seeks to address the unmet need for better animal models for AL amyloidosis, the most common of the systemic amyloidoses in U.S. citizens. It will build upon our initial experience generating animal models, with support of a P01 for studies of "Immunoglobulin Light Chain Fibrillogenesis". We will use a novel vector that causes the Myc oncogene to be expressed in a tissue-specific and stage-specific fashion in terminally differentiating B cells, leading to poly- and then mono-clonal expansion of plasma cells. By engineering the vector to also synthesize a human amyloidogenic immunoglobulin light chain, we hope to replicate the human disease AL amyloidosis. Mice will be characterized and used to study disease pathogenesis and treatment. To carry out this project, we will require the assistance of an additional laboratory technician, postdoctoral fellow and graduate student and will augment the use of existing Core facilities staffed by animal technicians and an expert transgenic technician.