Genetic Determinants of Susceptibility to Kidney Disease in African Americans

非裔美国人肾病易感性的遗传决定因素

• 批准号: 7936333
• 负责人: THOMAS M COFFMAN
• 金额: $ 49.94万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936333
• 关键词: Address; Affect; African American; Alleles; American; Animal Model; Area; Clinical; Code; Development; Disease; ES Cell Line; Embryo; End stage renal failure; Engineering; Ensure; European; Exons; Generations; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Haplotypes; Health Services Accessibility; Human; Human Genetics; Hypertension; Individual; Injury; Introns; Kidney; Kidney Diseases; Knowledge; Lead; Link; Location; Methods; Minor; Mus; Myosin Heavy Chains; National Institute of Diabetes and Digestive and Kidney Diseases; Pathogenesis; Patients; Pattern; Physiological; Predisposition; Prevention; Process; Property; Proteins; Recovery; Research; Resistance; Risk; Role; Sampling; Socioeconomic Status; Specific qualifier value; Testing; Time; Tissues; Translating; Translational Research; Variant; animal model development; embryonic stem cell; experience; genetic association; genetic variant; homologous recombination; human DNA; improved; in vivo; mouse genome; mouse model; nephrogenesis; non-muscle myosin; novel; prevent; public health relevance; response; stem; tool

DESCRIPTION (provided by applicant): The risk for developing end-stage renal disease (ESRD) in African Americans is more than 3-fold higher than European Americans. This disproportionate risk is apparent for virtually all forms of kidney disease, but only a minor portion can be explained by socio-economic status and/or poor access to health care. Recent studies have identified polymorphisms in the gene encoding MYH9, a non-muscle myosin heavy chain that are associated with susceptibility to ESRD in African-Americans, explaining a substantial component of the attributable risk. Identification of this association between MYH9 variants and risk for ESRD is a major breakthrough. However, since these variants do not include significant changes in the sequence of exons or intron:exon junctions, the major research opportunity and scientific knowledge gap is to determine the causal mechanisms connecting MYH9 polymorphisms with the pathogenesis of kidney injury. Because MYH9 is a structural, intra-cellular protein, its role in the pathobiology of kidney disease will be difficult to study in patients through analysis of clinical samples. Nonetheless, translating the discovery of this genetic association into improved prevention and treatment for individuals at risk will require precise understanding of the mechanisms whereby these genetic variants influence the course of kidney disease. Accordingly, we propose to generate mouse lines in which human MYH9 haplotypes are inserted into the syntenic location of the mouse genome in the absence of the mouse orthologue. These lines will be generated using a novel and robust 2-step method wherein the mouse locus is excised in embryonic stem (ES) cells in a manner that allows rapid introduction of the analogous human gene directly into the deleted locus. Our experience in developing this method indicates that the inserted human gene retains its key functional and regulatory properties in the mouse. Thus, development of these animal models will provide a unique opportunity for studying the physiological consequences of human MHY9 haplotypes in vivo under precisely controlled genetic and environmental conditions in order to understand their contributions to the development of kidney injury. We have assembled a highly accomplished, multi-disciplinary team to ensure that the generation and initial characterization of these mouse lines can be completed within the two-year period specified by the Recovery Act. These animal models will be powerful tools for identifying new strategies for preventing ESRD in African Americans. PUBLIC HEALTH RELEVANCE: African Americans have a significantly greater risk of developing end-stage renal disease (ESRD) than European Americans. While this disparity has been recognized for some time, its cause was not known. Recently, two groups independently identified associations between risk for ESRD in African-Americans and variations in a gene called MYH9. However, it is not clear how the variation in this gene could lead to kidney disease. In the studies we are proposing, we plan to generate mice in which the human MYH9 variants are inserted into the mouse genome where they can be studied under precisely controlled genetic and environmental conditions in order to understand their contributions to the development of kidney injury. These animal models will be powerful tools for identifying new strategies for preventing ESRD in African Americans.

描述（由申请人提供）：在非洲裔美国人中患上终末期肾脏疾病（ESRD）的风险比欧洲人高3倍以上。对于几乎所有形式的肾脏疾病，这种不成比例的风险都是显而易见的，但是只能通过社会经济地位和/或获得医疗保健的机会来解释一小部分。最近的研究已经确定了编码MYH9的基因中的多态性，这是一种非肌肉肌球蛋白重链，与非裔美国人的ESRD易感性相关，解释了可归因的风险的实质性组成部分。识别MYH9变体与ESRD风险之间的关联是一个重大突破。但是，由于这些变体不包含外显子或内含子序列的重大变化：外显子连接处，因此主要的研究机会和科学知识差距是确定将MYH9多态性与肾脏损伤发病机理相关的因果机制。由于MYH9是一种结构性的细胞内蛋白，因此通过分析临床样品，在患者中很难在肾脏疾病病理学中的作用。尽管如此，将这种遗传关联的发现转化为改善的预防和对处于危险的个体的治疗将需要精确理解这些遗传变异的机制，这些机制会影响肾脏疾病的进程。因此，我们建议在没有小鼠直系同源物的情况下将人MyH9单倍型插入小鼠基因组的同步位置中的小鼠线。这些线将使用一种新颖而健壮的2步方法生成，其中在其中，在胚胎茎（ES）细胞中切除小鼠基因座的方式，该方法允许将类似的人基因直接直接引入已删除的基因座中。我们在开发这种方法方面的经验表明，插入的人基因保留了小鼠中其关键功能和调节特性。因此，这些动物模型的开发将为精确控制的遗传和环境条件研究人类MHY9单倍型的生理后果提供独特的机会，以了解它们对肾脏损伤发展的贡献。我们已经组建了一个高度成就，多学科的团队，以确保可以在《恢复法》指定的两年内完成这些鼠标线的生成和初始表征。这些动物模型将是确定防止非裔美国人ESRD的新策略的强大工具。 公共卫生相关性：非洲裔美国人比欧洲人的末期肾脏疾病（ESRD）的风险要大得多。尽管这种差距已被认可了一段时间，但其原因却尚不清楚。最近，两个小组独立地确定了非裔美国人ESRD风险与称为MYH9的变化之间的关联。但是，尚不清楚该基因的变异如何导致肾脏疾病。在我们提出的研究中，我们计划生成小鼠，其中人类MYH9变体被插入小鼠基因组中，可以在精确控制的遗传和环境条件下进行研究，以了解它们对肾脏损伤发展的贡献。这些动物模型将是确定防止非裔美国人ESRD的新策略的强大工具。