Molecular hematology and sickle mouse core

总结 转基因镰状小鼠为严格研究镰状细胞的机制提供了前所未有的机会。 疾病在一个受控的实验模型。其中最常见的研究是表达小鼠 与人HbS一起沿着的珠蛋白链，包括NY1DD和S + SAnt。这些模型显示适度或无慢性 贫血表达人HbS而不表达小鼠α和β珠蛋白链的常用小鼠模型 是BERK和Townes转基因镰刀小鼠。在这两种转基因模式中，汤斯镰刀是“敲入”的。 在小鼠珠蛋白基因的位置插入（敲入）人α和β珠蛋白基因的模型 店这两种模型表现出镰状细胞病的严重特征，包括血液学疾病、器官损害、贫血和贫血。 损伤和缩短寿命类似于临床疾病。Townes和BERK纯合子小鼠 表现出炎症、氧化应激和内皮活化，与报告的 镰状细胞病患者。这两种小鼠似乎都是分析各种疾病的合适模型。 镰状细胞病的并发症以前没有任何镰状小鼠模型的群体 在非洲的任何一个机构里。这种技术限制总是使非洲科学家处于一个主要的地位。 不利的贡献知识，以促进我们的理解是最普遍的疾病， 他们的大陆。在非洲大陆，基因组学技术也普遍缺乏， 这就造成了上述限制。本申请的PI具有广泛的人类经验 分子基因组学、血液学和转基因镰状小鼠技术。PI已经建立了稳定的 在埃默里大学和最近在埃默里大学的汤斯转基因镰刀小鼠模型的殖民地， 匹兹堡。匹兹堡大学的殖民地已经发展成为世界上最大的殖民地之一， 不仅对于匹兹堡大学的研究人员来说，而且对于美国的研究人员来说，都是一个有用的资源 其他美国机构。PI将利用匹兹堡大学的镰状鼠群来建立 加纳大学野口纪念医学研究所的非洲第一个镰状细胞小鼠群 作为SickleGenAfrica H3Africa合作中心的共享科学核心设施进行研究。的目标 H3非洲合作中心的三个研究项目是确定全基因组遗传风险 SCD患者多器官功能障碍的相关因素。虽然每个项目都计划复制 在一个非洲人群（例如西非人）中发现的遗传相关性， 尽管非洲大陆至少有一个不同的部分（如东非），但研究结果仍将保持相关性。的 镰状小鼠核心将为加纳和其他参与地点的研究人员和学生提供（例如， 尼日利亚）的第一次机会，功能验证这种协会在一个既定的模式动物。 !

Summary Transgenic sickle mice offer unparalleled opportunities to rigorously examine mechanisms of sickle cell disease in a controlled experimental model. Among the most commonly studied are mice expressing mouse globin chains along with human HbS, including NY1DD and S+SAnt. These models show modest or no chronic anemia. Commonly used mouse models that express human HbS without mouse alpha and beta globin chains are BERK and Townes transgenic sickle mice. Of the two the Townes sickle transgenic models is “knock-in” model where human alpha and beta-globin genes are inserted (knocked-in) in place of mouse globin genes chains. These two models exhibit severe features of sickle cell disease including hematologic disease, organ damage and shortened life span similar to the clinical disease. Both Townes and BERK homozygous mice exhibit inflammation, oxidative stress, and endothelial activation, similar to the pathobiology reported for patients with sickle cell disease. Both of these mice appear to be suitable models to analyze a variety of complications seen in sickle cell disease. There has not previously been any colony of the sickle mouse model established in any institution in Africa. This technological limitation invariably puts African scientists at a major disadvantage in contributing knowledge to advancing our understanding of a disorder that is most prevalent on their continent. There is a similar dearth in genomics technology generally on the African continent, which compounds the aforementioned limitation. The PI of this application has widespread experience in human molecular genomics, hematology and transgenic sickle mouse technology. The PI has established stable colonies of the Townes' transgenic sickle mouse model at Emory University and more recently at the University of Pittsburgh. The colony at the University of Pittsburgh has grown to become one of the largest in the world, and a useful resource not only for investigators in the University of Pittsburgh, but for also for investigators in other US institutions. The PI will leverage the sickle mouse colony at the University of Pittsburgh to establish the first colony of sickle cell mice in Africa, at the University of Ghana's Noguchi Memorial Institute for Medical Research as a shared scientific core facility of the SickleGenAfrica H3Africa Collaborative Center. The goals of the three research projects of the H3Africa Collaborative Center are to define the genome-wide genetic risk factors of organ dysfunction in multiple organ systems in SCD. While each project is planning to replicate genetic associations discovered in one African population (e.g. West Africans), in a cohort of patients from at least one different part of the continent (e.g. East Africa), the findings will nonetheless remain correlative. The sickle mouse core will offer investigators and students in Ghana and in the other participating sites (e.g. Nigeria) the first opportunity to functionally validate such associations in an established model animal. !