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: 8608565
• 负责人: Dale L Dorsett
• 金额: $ 26.74万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8608565
• 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; 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.

项目III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， 果蝇的发育这解决了该计划的长期目标，解释病因， 科尔内利亚德兰格综合征（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性缺陷。CdLS是由三个编码姐妹花的基因突变引起的。 染色单体凝聚蛋白：NIPBL，Smc 1和Smc 3。Smc 1和Smc 3是粘附素复合物的一部分， 将姐妹染色单体粘合在一起，NIPBL将粘着蛋白放在染色体上。CdLS突变弱减少 凝聚蛋白活性，并且不会导致明显的染色体凝聚缺陷。果蝇的早期研究 结果表明，cohesin也调节基因表达。因此，该计划正在测试的想法， 基因表达导致CdLS结构性出生缺陷。数据显示NIPBL和粘附素阳性， 负调控人类、小鼠、斑马鱼和果蝇中的数百个基因。目前还不清楚 靶基因的类型，或者基因表达差异的数量或大小导致发育缺陷。 缺陷也不清楚细胞增殖的减少是否有助于缓慢的生长或结构的诞生 CdLS中的缺陷。这个问题源于发现粘附素调节已知的 在人类、小鼠、斑马鱼和果蝇中的生长、细胞增殖和蛋白质合成的调节剂。 项目111将解决两个具体目标中尚未解答的关键问题：（1）NIPBL和粘附素的影响 将测量剂量对幼虫成虫盘发育过程中基因表达动态的影响 全基因组的研究。通过表达筛选鉴定的靶基因的组合将被 测试它们的表达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中细胞增殖和生长的影响，以及调节 增长将被量化。生长调节剂的潜在作用将在遗传学上进行测试。增加 了解粘附素在基因表达和发育中的作用，将有望导致更好的诊断， 治疗CdLS。 相关性（参见说明）： 科尔内利亚德兰格综合征（CdLS）是一种遗传性疾病，可导致生长缓慢，精神障碍， 面部手臂手部内脏和心脏的异常该项目将使用果蝇作为模型系统， 发现CdLS中的基因变化如何导致这些问题。这些研究的信息将有助于 开发更好的诊断和治疗CdLS的方法。