PROJECT III: A Drosophila Model for Cornelia de Lange Syndrome

项目 III：Cornelia de Lange 综合征的果蝇模型

• 批准号: 8378233
• 负责人: Dale L Dorsett
• 金额: $ 26.31万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8378233
• 关键词: 10q25; 5p13.1; Address; Adipose tissue; Affect; Binding; Biological Models; Bruck-de Lange syndrome; CSPG6 gene; Cell Lineage; Cell Proliferation; Cell division; Cells; Chemicals; Chromosome Cohesion; Chromosome Segregation; Chromosomes; Complex; Congenital Abnormality; DNA; Data; Defect; Development; Diagnosis; Diagnostic; Drosophila genus; Eating; Etiology; Eye; Eye Development; Face; Fat Body; Figs - dietary; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Glues; Goals; Growth; Hand; Heart; Hereditary Disease; Human; Hypersensitivity; Impairment; In Situ Hybridization; Individual; Instruction; Insulin; Insulin Receptor; Knowledge; Lead; Learning; Limb structure; Liver; Measures; Methods; Modeling; Mus; Mutation; Neuraxis; Online Mendelian Inheritance In Man; Organ; Organism; Pathway interactions; Polycomb; Principal Investigator; Protein Biosynthesis; Proteins; Psyche structure; RNA; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Sister Chromatid; System; Testing; Therapeutic; Tissues; Transcript; Wing; Work; Xp11.22; Zebrafish; arm; base; cell growth; cohesin; cohesion; dosage; gene discovery; genome-wide; imaginal disc; improved; in vivo; in vivo Model; induced pluripotent stem cell; mouse development; nutrition; nutrition related genetics; postnatal; prenatal; programs; research study; transcription factor

Project Ill's long-term goal is to learn how sister chromatid cohesion proteins regulate gene expression and development in Drosophila. This addresses the Program's long-term goal of explaining the etiology of Cornelia de Lange syndrome (CdLS). CdLS shows many birth defects, including slow growth, mental deficits and structural defects in limbs and organs. CdLS is caused by mutations in three genes encoding sister chromatid cohesion proteins: NIPBL, Smc1 and Smc3. Smc1 and Smc3 are part of the cohesin complex that glues sister chromatids together, and NIPBL puts cohesin on chromosomes. CdLS mutations weakly reduce cohesion protein activity, and do not cause overt chromosome cohesion defects. Early work in Drosophila showed that cohesin also regulates gene expression. This Program is thus testing the idea that changes in gene expression cause CdLS structural birth defects. The data show that NIPBL and cohesin positively and negatively regulate hundreds of genes in human, mouse, zebrafish and Drosophila. It remains unknown what types of target genes, or what numbers or sizes of gene expression differences cause the developmental defects. It is also unknown if decreased cell proliferation contributes to the slow growth or structural birth defects in CdLS. This question arises from the discovery that cohesin regulates expression of known regulators of growth, cell proliferation and protein synthesis, in human, mouse, zebrafish and Drosophila. Project 111 will address key unanswered questions in two Specific Aims: (1) Effects of NIPBL and cohesin dosage on the dynamics of gene expression during development of larval imaginal discs will be measured genome-wide using microarrays. Combinations of target genes identified by the expression screens will be tested to see if changes in their expression cause developmental defects. (2) Effects of NIPBL and cohesin dosage and nutrtion on cell proliferation and growth in larval tissues, and expression of genes that regulate growrth will be quantified. The potential roles of growth regulators will be tested genetically. Increased knowledge of cohesin's roles in gene expression and development will hopefully lead to better diagnosis and therapy for CdLS. RELEVANCE (See instructions): Cornelia de Lange syndrome (CdLS) is genetic disease that causes slow growth, mental impairment, and abnormalities in the face, arms, hands, gut and heart. This project will use fruit flies as model system to discover how the gene changes in CdLS cause these problems. The information from these studies will help develop better methods for diagnosing and treating CdLS.

Ill项目的长期目标是了解姐妹染色单体凝聚蛋白如何调节基因表达和 果蝇的发育。这解决了该计划解释疾病病因的长期目标 Cornelia de Lange综合征(CDLS)。CDLS显示了许多出生缺陷，包括生长缓慢，智力缺陷 以及四肢和器官的结构性缺陷。CDLS是由编码姐妹基因的三个基因突变引起的。 染色单体结合蛋白：NIPBL、Smc1和Smc3。Smc1和Smc3是粘附素复合体的一部分， 将姐妹染色单体粘合在一起，NIPBL将粘附素添加到染色体上。CDLS突变微弱减少 凝聚力蛋白活性强，不会引起显性的染色体凝聚力缺陷。果蝇的早期工作 表明粘附素也调节基因的表达。因此，该计划正在测试这样一种想法，即在 基因表达导致CDLS结构先天缺陷。数据显示NIPBL和粘附素呈正相关 对人类、小鼠、斑马鱼和果蝇的数百个基因进行负调控。目前还不清楚是什么 靶基因的类型，或基因表达差异的数量或大小导致发育 缺陷。细胞增殖减少是否导致生长缓慢或结构性出生也是未知的。 CdLS中的缺陷。这个问题产生于粘附素调节已知基因表达的发现 人类、小鼠、斑马鱼和果蝇的生长、细胞增殖和蛋白质合成的调节剂。 项目111将在两个具体目标中解决尚未回答的关键问题：(1)NIPBL和凝聚素的影响 将测量幼虫成像盘发育过程中基因表达动态的剂量 使用微阵列在全基因组范围内。通过表达筛选确定的目标基因的组合将是 测试以确定它们表达的变化是否会导致发育缺陷。(2)NIPBL和粘附素的作用 剂量和营养对幼虫组织中细胞增殖和生长的影响以及调节基因的表达 增长将被量化。增长调节器的潜在作用将从基因上受到考验。增加了 了解粘附素在基因表达和发育中的作用有望带来更好的诊断和 CDLS的治疗。 相关性(请参阅说明)： Cornelia de Lange综合征(CDLS)是一种遗传性疾病，会导致生长迟缓、智力障碍和 面部、手臂、手、内脏和心脏的异常。本项目将以果蝇为模型系统， 了解CDL中的基因变化如何导致这些问题。来自这些研究的信息将会有所帮助 开发更好的诊断和治疗CDLS的方法。