Molecular hematology and sickle mouse core

分子血液学和镰状鼠核心

• 批准号: 10240495
• 负责人: Phyllis G Addo
• 金额: $ 15.64万
• 依托单位: UNIVERSITY OF GHANA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240495
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Africa; African; Anemia; Animal Model; Animals; Biochemical Genetics; Biological Assay; Blood Vessels; Breeding; Caliber; Candidate Disease Gene; Cardiovascular system; Cerebral Malaria; Chronic; Clinical; Collaborations; Complication; Core Facility; Country; Data; Development; Disadvantaged; Disease; Endothelium; Enzyme-Linked Immunosorbent Assay; Exhibits; Experimental Models; Ferritin; Fetal Hemoglobin; Functional disorder; Genes; Genetic Techniques; Genetic Variation; Genetic study; Genomics; Genotype; Ghana; Globin; Goals; Haptoglobins; Hematological Disease; Hematology; Hemoglobin; Hemolysis; Hemopexin; High Pressure Liquid Chromatography; Human; Image; Individual; Inflammation; Injury to Kidney; Institute of Medicine (U.S.); Institutes; Institution; Knock-in; Knowledge; Left; Left Ventricular Mass; Longevity; Malaria; Measurement; Measures; Medical Research; Medical center; Microscopic; Mitral Valve; Modeling; Molecular; Mus; Myocardial dysfunction; Nigeria; Organ; Oxidative Stress; Pathogenesis; Patients; Phenotype; Physiological; Plasma; Population; Pre-Clinical Model; Proteins; Pulmonary Hypertension; Pulse Oximetry; Reporting; Research; Research Personnel; Research Project Grants; Research Proposals; Resources; Reticulocytosis; SNP genotyping; Sampling; Scientist; Severity of illness; Sickle Cell; Sickle Cell Anemia; Single Nucleotide Polymorphism; Site; Standardization; Students; Sudden Death; System; Techniques; Technology; Therapeutic; Time; Transgenic Mice; Transgenic Model; Transgenic Organisms; Translational Research; Ultrasonography; Universities; Variant; Ventricular; acute chest syndrome; alpha Globin; alpha-1-microglobulin; base; beta Globin; body system; cardiovascular imaging; cohort; conditional knockout; design; efficacy evaluation; experience; experimental study; functional outcomes; genetic association; genetic risk factor; genome-wide; heart function; hemodynamics; imaging facilities; imaging system; improved; in vivo; lung injury; molecular hematology; molecular imaging; mouse model; multiorgan damage; preclinical study; pressure; pulmonary function; sickling; therapeutic development

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. !

摘要 转基因镰刀鼠为严格研究镰刀细胞的机制提供了无与伦比的机会 疾病在受控的实验模型中。其中最常见的研究是小鼠表达小鼠 珠蛋白链与人HBs，包括NY1DD和S+SANT。这些模型显示出适度或没有慢性 贫血。表达不含小鼠α和β珠蛋白链的人HBs的常用小鼠模型 是Berk和Townes转基因镰刀鼠。在这两种转基因模型中，汤斯镰刀是“敲入”的。 人类α和β珠蛋白基因插入(敲入)取代小鼠珠蛋白基因的模型 锁链。这两种模型表现出严重的镰状细胞病特征，包括血液病、器官疾病 损伤和寿命缩短类似于临床疾病。Townes和Berk纯合子小鼠 表现出炎症、氧化应激和内皮激活，类似于报告的病理生物学 患有镰状细胞病的患者。这两只小鼠似乎都是分析各种 镰状细胞病的并发症。以前还没有发现过任何镰刀鼠模型。 在非洲的任何机构设立。这种技术限制总是让非洲科学家处于一种重大的 贡献知识来促进我们对一种最常见的疾病的理解是不利的 他们的大陆。在非洲大陆，基因组学技术普遍也存在类似的匮乏， 这加剧了上述限制。这个应用程序的PI在人类中具有广泛的经验 分子基因组学、血液学和转基因镰刀鼠技术。PI已经建立了稳定 埃默里大学和最近埃默里大学的汤斯转基因镰刀鼠模型的克隆 匹兹堡的。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， 这不仅是匹兹堡大学研究人员的有用资源，也是 其他美国机构。PI将利用匹兹堡大学的镰刀鼠群体来建立 在加纳大学野口医学纪念研究所，非洲第一批镰状细胞小鼠 研究作为SickleGenAfrica H3非洲合作中心的共享科学核心设施。的目标 H3非洲合作中心的三个研究项目是定义全基因组范围的遗传风险 SCD患者多脏器系统功能障碍的相关因素分析虽然每个项目都计划复制 在一个非洲人群(例如西非人)中发现的遗传关联，在来自At的一群患者中发现 尽管非洲大陆至少有一个不同的地区(例如东非)，但这些研究结果仍将相互关联。这个 镰刀鼠核心将为加纳和其他参与地点的调查人员和学生提供(例如： 尼日利亚)首次有机会在已建立的模型动物中验证这种联系。 好了！