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Molecular hematology and sickle mouse core

分子血液学和镰状鼠核心

基本信息

批准号：
10000992
负责人：
Phyllis G Addo
金额：
$ 9.37万
依托单位：
UNIVERSITY OF GHANA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000992
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 Respiratory physiology 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 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 sickling therapeutic development

项目摘要

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. !

总结