Mouse Models of Functional Insertion Polymorphisms

功能插入多态性的小鼠模型

• 批准号: 8812892
• 负责人: KATHLEEN H BURNS
• 金额: $ 30.78万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-02 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812892
• 关键词: ARID Domain; Acute Lymphocytic Leukemia; Affect; Aldosterone; Alleles; Angiotensins; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Lymphocytes; Binding; Biomedical Research; Blood Pressure; Blood Vessels; Bradykinin; Chromatin Structure; Chromosomes, Artificial, Yeast; Clinical; Cloning; DNA Transposable Elements; Development; Diagnosis; Disease; Early Diagnosis; Elements; Enzyme Gene; Enzymes; Feasibility Studies; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Goals; Haplotypes; Health; Homeostasis; Human; Human Genetics; Inherited; Introns; Junk DNA; Knowledge; Laboratories; Link; Linkage Disequilibrium; Malignant Childhood Neoplasm; Marrow; Measures; Methods; Modeling; Molecular Biology; Mus; Nucleotides; Other Genetics; Pathogenesis; Patients; Peptidyl-Dipeptidase A; Phase; Phenotype; Physiological; Positioning Attribute; Prevention; Proteins; Renin; Research Design; Research Personnel; Resources; Risk; Role; Serum; Signal Transduction; Source; Study models; System; Testing; Transcript; Transgenes; Transgenic Mice; Untranslated RNA; Variant; Work; base; blood pressure regulation; clinical assay development; disorder risk; enzyme activity; experience; follow-up; gene function; genetic variant; genome wide association study; human disease; in vivo; innovation; mRNA Expression; mouse model; prototype; research study; synthetic biology; trait; transcription factor; transposon/insertion element; yeast genetics

DESCRIPTION (provided by applicant): Our genomes are mostly made up of repetitive 'junk DNA' derived from insertions of mobile elements. Our group has developed methods to identify polymorphic insertions of these understudied sequences, demonstrated they are major sources of structural variation our genome, and found they occur frequently in linkage disequilibrium with trait associated SNPs identified by GWAS. Experiments by others and characterizations of the non-random distribution of mobile DNAs in genomes indicate they have significant potential to effect gene function. Our overarching hypothesis is that a subset of Alu insertions - the most prevalent and polymorphic mobile DNAs in humans - has phenotypic consequence. Our specific objectives are to isolate and characterize the effects of two polymorphic Alu insertions in allelogenic transgenic mouse models. The first insertion polymorphism to be studied is an intronic Alu 287bp in the angiotensin converting enzyme (ACE) gene locus. ACE encodes a key component of the renin-angiotensin-aldosterone blood pressure control system and is also involved in vascular homeostasis through degradation of bradykinin; the Alu is a well-studied marker of reduced ACE enzyme levels and presumed to be functional, although this has not been directly tested. The second polymorphism we propose to study is a 168bp intronic Alu insertion in the AT-rich interactive domain-containing protein 5B (ARID5B) locus. We recently associated this polymorphic Alu with risk for developing the most common childhood cancer, precursor B-cell acute lymphoblastic leukemia (ALL). The proposed studies will be the first to isolate and measure effects common, naturally-occurring TE insertion polymorphisms in vivo and to generate models to study mechanisms of these effects. More broadly, the work will provide a study design for mouse modeling in GWAS follow-up and begin work to make available an allelogenic YAC resource for studying functions of other Alu insertions.

描述（由申请人提供）：我们的基因组主要由重复的“垃圾DNA”组成，这些“垃圾DNA”来源于移动的元件的插入。我们的小组已经开发了方法来识别这些未充分研究的序列的多态性插入，证明它们是我们基因组结构变异的主要来源，并发现它们经常与GWAS识别的性状相关SNP连锁不平衡。其他人的实验和对基因组中移动的DNA的非随机分布的描述表明，它们具有影响基因功能的巨大潜力。我们的首要假设是，一个子集的Alu插入-最普遍和多态性的移动的DNA在人类-有表型的后果。我们的具体目标是分离和表征两个多态性的Alu插入在等位基因转基因小鼠模型的影响。第一个要研究的插入多态性是在血管紧张素转换酶（ACE）基因位点的内含子Alu 287 bp。ACE编码肾素-血管紧张素-醛固酮血压控制系统的关键组分，并且还通过缓激肽的降解参与血管稳态; Alu是ACE酶水平降低的充分研究的标志物，并且推测是功能性的，尽管这尚未被直接测试。第二个多态性，我们建议研究的是一个168 bp的内含子中的Alu插入在AT丰富的相互作用结构域的蛋白质5 B（ARID 5 B）位点。我们最近将这种多态性Alu与发展最常见的儿童癌症前体B细胞急性淋巴细胞白血病（ALL）的风险联系起来。拟议的研究将是第一个分离和测量体内常见的自然发生的TE插入多态性的影响，并生成模型来研究这些影响的机制。更广泛地说，这项工作将为GWAS后续的小鼠建模提供研究设计，并开始工作，为研究其他Alu插入的功能提供等位基因YAC资源。