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: 8826150
• 负责人: Dale L Dorsett
• 金额: $ 27.31万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826150
• 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; Protein Biosynthesis; Proteins; Psyche structure; RNA; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Sister Chromatid; Structural Congenital Anomalies; Structural defect; 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.

Project Ill 的长期目标是了解姐妹染色单体粘合蛋白如何调节基因表达和 果蝇的发育。这解决了该计划的长期目标，即解释病因 科妮莉亚·德·朗格综合征（CdLS）。 CdLS 显示出许多出生缺陷，包括生长缓慢、智力缺陷 以及四肢和器官的结构缺陷。 CdLS 是由编码姐妹的三个基因突变引起的 染色单体粘合蛋白：NIPBL、Smc1 和 Smc3。 Smc1 和 Smc3 是粘连蛋白复合物的一部分 将姐妹染色单体粘合在一起，NIPBL 将粘连蛋白放在染色体上。 CdLS突变微弱减少 粘合蛋白活性，并且不会引起明显的染色体粘合缺陷。果蝇的早期工作 表明粘连蛋白还调节基因表达。因此，该计划正在测试以下想法： 基因表达导致CdLS结构出生缺陷。数据显示，NIPBL 和 cohesin 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。目前尚不清楚是什么 目标基因的类型，或者基因表达差异的数量或大小导致发育 缺陷。尚不清楚细胞增殖减少是否会导致生长缓慢或结构诞生 CdLS 的缺陷。这个问题源于粘连蛋白调节已知的表达的发现 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因子。 项目 111 将解决两个具体目标中尚未解答的关键问题：(1) NIPBL 和粘连蛋白的影响 将测量幼虫成虫盘发育过程中基因表达动态的剂量 使用微阵列进行全基因组分析。通过表达筛选鉴定的靶基因的组合将是 进行测试以确定其表达的变化是否会导致发育缺陷。 (2) NIPBL和cohesin的作用 剂量和营养对幼虫组织细胞增殖和生长以及调节基因表达的影响 增长将被量化。生长调节剂的潜在作用将通过基因测试。增加 了解粘连蛋白在基因表达和发育中的作用将有望带来更好的诊断和 CdLS 的治疗。 相关性（参见说明）： Cornelia de Lange 综合征 (CdLS) 是一种遗传性疾病，会导致生长缓慢、精神障碍和 面部、手臂、手、肠道和心脏异常。该项目将使用果蝇作为模型系统 了解 CdLS 中的基因变化如何导致这些问题。这些研究中的信息将有助于 开发更好的方法来诊断和治疗 CdLS。