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”来自移动元素的插入。我们的小组开发了鉴定这些研究序列的多态性插入的方法，证明它们是我们基因组结构变异的主要来源，发现它们经常出现在与GWAS鉴定的特征相关的SNP的连锁不平衡中。他人的实验以及基因组中移动DNA的非随机分布的表征表明它们具有影响基因功能的巨大潜力。我们的总体假设是，ALU插入的子集（人类中最普遍，最普遍，多态性的移动DNA）具有表型后果。我们的具体目标是隔离并表征在类别性转基因小鼠模型中两种多态性ALU插入的影响。要研究的第一个插入多态性是血管紧张素转化酶（ACE）基因基因座中的内含子ALU 287bp。 ACE编码肾素 - 血管紧张素 - 醛固酮血压控制系统的关键组成部分，还通过降解Bradykinin参与了血管稳态； ALU是降低的ACE酶水平的良好的标记，并假定是功能性的，尽管尚未直接测试。我们建议研究的第二个多态性是在富含富含互动结构域的蛋白5B（ARID5B）基因座中的168bp内含子ALU插入。我们最近将这种多态性ALU与发展最常见的儿童癌，前体B细胞急性淋巴细胞白血病（ALL）的风险。拟议的研究将是第一个隔离和测量效应的效果，在体内插入多态性，并生成模型以研究这些作用的机制。更广泛地说，这项工作将为GWAS随访中的鼠标建模提供研究设计，并开始工作，使其成为研究其他ALU插入功能的全体元素YAC资源。