Resource for marking clones on the fly 4th chromosome

用于在第四条染色体上标记克隆的资源

基本信息

批准号：
9372952
负责人：
STUART J NEWFELD
金额：
$ 19.68万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2019-07-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9372952
关键词：
Activins Adult Area Attention BCL9 gene Biological Biology Brain Cell Communication Cell physiology Cells Chromosome Segregation Chromosomes Communities Development Disease Distal Drosophila genus Drosophila melanogaster Enteral FOXL1 gene Family Funding Future GDF8 gene Genes Genetic Genetic Recombination Health Human Institutes Intestines Knowledge Letters Ligands Light Mammals Maps Memory Loss Methods Molecular Monoclonal Antibody R24 Mushroom Bodies Mutagenesis Mutation Mutation Analysis National Institute of General Medical Sciences National Institute of Neurological Disorders and Stroke Neuraxis Neurobiology Neuroglia Neurons Oncogenes Orthologous Gene Pathway interactions Physiology Research Personnel Resource Development Resources Role SOX5 gene Scientist Signal Transduction Site Stem cells Syndrome System Systems Development Testing Transducers Transforming Growth Factor beta Transgenes Translating United States National Institutes of Health Work activin B alpha secretase arm autosome fly frontier genetic analysis genetic approach inhibin B innovation insight interest loss of function mutation mutant nervous system disorder relating to nervous system response smoothened signaling pathway tool virtual ward

项目摘要

Resource for marking clones on the fly 4th chromosome For over a century, studies employing Drosophila melanogaster have resulted in significant advances in our understanding of highly conserved cellular processes and signaling systems. In the area of human health, Drosophila genetics has been an effective means for identifying disease-associated genes and for providing insights into their mechanism of action. The fourth chromosome (IV) is the final frontier for genetic analysis in Drosophila. Small and devoid of recombination IV has been largely ignored. Nevertheless, the long arm of IV contains roughly 105 genes. 55% of these genes have obvious human orthologs and 67% of the human genes have a disease association. A complete understanding of multicellularity requires the genetic analysis of mutations in these genes. Somatic and germline clones are established tools for studying the functions of lethal mutations in flies. The MARCM system for tracking clones of mutant cells he has been widely employed to study central nervous system development and adult intestinal stem cells. However, MARCM is not useable on IV due to the lack of appropriate chromosomes. As a resource for the Drosophila community whose investigators are funded by virtually all of the NIH Institutes and Centers, we propose a collaborative R21 (in response to PAR-16-141) to generate the necessary chromosomes for MARCM-IV. Our two labs are currently NIH funded for studies of TGF-β signaling and have worked together previously on the role of the Sno oncogene in TGF-β signal transduction. We will employ an innovative strategy integrating molecular methods (Crisper-Cas9) with genetics (X to autosome jumping). MARCM-IV will then be tested in studies of TGF-β signaling in the mushroom body and the enteric neurons of the larval brain. The Specific Aims of this project are: Aim1 Resource Development: To create the unique fourth chromosomes necessary for MARCM-IV. Aim2 Discovery: Proof of principal studies will utilize MARCM-IV to generate marked clones for three mutant genes. These are the TGF-β ligands activin-β and myoglianin and the Smad-interacting signal transducer dCORL (fussel in Flybase). These applications of MARCM-IV will advance our knowledge of molecular mechanisms in the TGF-β pathway, neural-glial interactions and the development/function of subesophageal neurons in the brain. The results should attract the attention of others in the Drosophila community whose interests encompass genes on IV. We will provide the MARCM-IV lines to any qualified investigator and evidence of community interest is already visible in letters appended to this proposal. Given that many of the genes on IV are conserved, new insights from MARCM-IV in flies can be readily translated into new hypotheses for normal development/physiology or diseases in humans. Looking ahead, it is likely our innovative approach can easily be expanded to an analysis of all genes on IV. The valuable community resource created by this project will be made freely available to all qualified researchers to facilitate our understanding of conserved features of developmental signaling and neurobiology impacting human health and disease.

果蝇第四号染色体上的克隆标记资源一个多世纪以来，利用果蝇的研究取得了重大进展了解高度保守的细胞过程和信号系统。果蝇遗传学已成为识别疾病相关基因并提供信息的有效手段。深入了解第四条染色体 (IV) 是遗传分析的最后前沿。果蝇。IV 较小且缺乏重组，但 IV 的长臂却在很大程度上被忽视了。包含大约 105 个基因，其中 55% 具有明显的人类直系同源基因，67% 具有人类基因。对多细胞性的全面了解需要进行遗传分析。这些基因的突变是研究其功能的既定工具。用于追踪突变细胞克隆的 MARCM 系统已被广泛应用。研究中枢神经系统发育和成体肠道干细胞然而，MARCM 不可用。由于缺乏适当的染色体而作为果蝇群落的资源。由于研究人员几乎得到所有 NIH 研究所和中心的资助，我们提出了一个协作 R21（在我们的两个实验室目前正在研究 PAR-16-141 的反应，以生成 MARCM-IV 所需的染色体。 NIH 资助了 TGF-β 信号传导的研究，并且之前就 Sno 的作用进行了合作我们将采用整合分子方法的创新策略。 (Crisper-Cas9) 与遗传学（X 到常染色体跳跃）将在 TGF-β 研究中进行测试。该项目的具体目标是蘑菇体和幼虫大脑的肠神经元中的信号传导。目标 1 资源开发：创建 MARCM-IV 所需的独特第四染色体。发现：主要研究证明将利用 MARCM-IV 生成三个突变基因的标记克隆。这些是 TGF-β 配体激活素-β 和肌胶质蛋白以及 Smad 相互作用信号转导器 dCORL （Flybase 中的 Fussel）。MARCM-IV 的这些应用将增进我们对分子机制的了解。 TGF-β 通路、神经胶质细胞相互作用以及食管下神经元的发育/功能结果应该引起果蝇界其他感兴趣的人的注意。我们将向任何合格的研究者提供 MARCM-IV 系和证据。鉴于 IV 上的许多基因，社区的兴趣已经在该提案所附的信件中体现出来。是保守的，MARCM-IV 在果蝇中的新见解可以很容易地转化为正常的新假设展望未来，我们的创新方法很可能可以轻松地解决人类的发育/生理或疾病问题。扩展到 IV 上所有基因的分析该项目创建的宝贵社区资源将是免费提供给所有合格的研究人员，以促进我们对保守特征的理解影响人类健康和疾病的发育信号和神经生物学。