Role of molecular recognition in retinal patterning and synaptic organization

分子识别在视网膜图案化和突触组织中的作用

基本信息

批准号：
7947549
负责人：
PETER Gerard FUERST
金额：
$ 24.27万
依托单位：
UNIVERSITY OF IDAHO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7947549
关键词：
Adhesions Alleles Alternative Splicing Amacrine Cells Biological Assay Biomedical Research Birth Cell Adhesion Molecules Cell Count Cell Death Cells Cellular Stress Chromosomes, Human, Pair 21 Code Communities Complex Coupled Cues Development Developmental Process Disease Down Syndrome Down Syndrome Cell Adhesion Molecule Drosophila genus Environment Etiology Eye Funding Genes Goals Homologous Gene Incidence Ligands Light Mediating Modeling Molecular Mus Mutant Strains Mice Mutation Nervous system structure Neurites Neurons Neurosciences Pathology Patients Pattern Phenotype Play Process Protein Isoforms Publishing RNA Splicing Regulation Reporting Research Research Proposals Retina Retinal Retinal Ganglion Cells Role Scientific Advances and Accomplishments Series Staging Stress Synapses System Testing Time Trisomy Universities Vertebrates Visual Washington Work axon guidance career cell type dosage gene function genetic resource light deprivation molecular recognition monocular mouse model mutant mouse model nervous system development neural patterning neurodevelopment neuron loss neuronal cell body overexpression prevent programs public health relevance receptor relating to nervous system research study

项目摘要

DESCRIPTION (provided by applicant): Candidate and Environment: Dr. Peter Fuerst will conduct the research contained within this proposal at Washington State University. Washington State University is an ideal environment in which to conduct advanced biomedical research using mouse models and in which to advance a research program. Research Proposal: The research we propose will use mouse models to identify the molecular mechanisms underpinning development of the retina. The mouse models, all developed by the applicant, include a conditional allele of the Down syndrome cell adhesion molecule, Dscam, as well as an allelic series of mouse mutant Dscam strains and a null allele of the Dscam homologue Dscam-like1 (Dscaml1). Dscam and Dscam- Like1 are essential for normal development of the nervous system and Dscam is proposed to contribute to the pathology of Down syndrome. In the retina, Dscam is required for soma mosaic spacing, regulation of cell number and neurite arborization and lamination. Our published results concerning Dscam and Dscaml1 are the first demonstrations of mutations found to ablate mosaic patterning and the first genes shown to mediate isoneuronal and heteroneuronal repulsion in vertebrates. Specific Aims: We propose to use the Dscam and Dscaml1 mutant mouse models to discover mechanisms underpinning development of the retina and to probe the function of Dscam in the mammalian nervous system. This will be accomplished by testing the following hypotheses detailed in this research proposal. Hypotheses: 1) We will test the hypothesis that DSCAM mediates multiple distinct functions using an allelic series and conditional allele of Dscam mouse mutant lines to genetically and temporally isolate Dscam-dependent developmental processes. 2) We will test the hypothesis that DSCAM mediates adhesion between cell types and repulsion within cell types and that DSCAM activity in the retina is mediated by homophillic interactions and not by a ligand-receptor mechanism by using a conditional allele coupled to cell type specific deletion. 3) We will test the hypothesis that Dscam and Dscaml1 regulate normal developmental cell death. Long-term goals: This research will uncover fundamental aspects of neural organization and provide the funding necessary for Dr. Fuerst to establish a successful academic career focused on hypothesis driven biomedical research. Significance: Neurite arborization, regulation of cell number and soma mosaic spacing are fundamental aspects of neurodevelopment that are not currently well understood at the molecular level in vertebrates. Our preliminary research indicates that DSCAM plays a vital role in mediating these processes in the mammalian nervous system. Identifying mechanisms by which DSCAM functions using a series of mouse mutant alleles and a conditional allele will contribute to our understanding of nervous system development and the causation of disorders associated with neural dysgenesis and also contribute valuable research models to the neuroscience community. PUBLIC HEALTH RELEVANCE: The primary goal of the proposed work is to understand how molecular recognition cues facilitate neural patterning. Research will focus on discovering the mechanisms by which two recognition cues; the Down Syndrome Cell Adhesion Molecule (Dscam) and its homologue Dscam-like1 (Dscaml1), mediate circuit formation within the retina. Both Dscam and Dscaml1 are required for neurite lamination, neurite arborization and regulation of cell number. Therefore, understanding the mechanism by which these molecules function will advance scientific understanding of neural development on multiple fronts. Furthermore, decreasing Dscam dosage decreases the incidence of retinal developmental cell death suggesting that the retina may provide an excellent system in which to model enhanced developmental cell death of neurons that occurs in Down syndrome patients, who overexpress Dscam as a result of Chromosome 21 trisomy.

描述（由申请人提供）：候选人和环境：彼得·富斯特博士将在华盛顿州立大学的此提案中进行研究。华盛顿州立大学是一个理想的环境，在其中使用鼠标模型进行高级生物医学研究，并在其中推进研究计划。研究建议：我们提出的研究将使用小鼠模型来确定视网膜发展的分子机制。所有由申请人开发的小鼠模型包括唐氏综合征细胞粘附分子，DSCAM的条件等位基因，以及一系列等位基因的小鼠突变体DSCAM菌株和DSCAM同源性DSCAM Like1（DSCAML1）的无效等位基因。 DSCAM和DSCAM-like1对于神经系统的正常发育至关重要，并提出DSCAM有助于唐氏综合症的病理。在视网膜中，DSCAM是SOMA镶嵌间距，细胞数和神经突化和层压的调节所必需的。我们关于DSCAM和DSCAML1的已发表的结果是消除镶嵌图案的突变的首次证明，并且显示出介导脊椎动物中介导的尿神经元和异源性抑制的第一个基因。具体目的：我们建议使用DSCAM和DSCAML1突变小鼠模型来发现视网膜开发的机制，并探究DSCAM在哺乳动物神经系统中的功能。这将通过测试本研究建议中详细介绍的以下假设来实现。假设：1）我们将检验以下假设：DSCAM使用DSCAM小鼠突变线的等位基因序列和条件等位基因介导了多个不同的功能，以遗传和时间分离出DSCAM依赖性的发育过程。 2）我们将测试以下假设：DSCAM在细胞类型中介导细胞类型和排斥之间的粘附，并且视网膜中的DSCAM活性是通过均匀相互作用而不是通过使用条件等位基因耦合到细胞类型特定特定缺失的条件等位基因来介导的，而不是通过配体受感受器机制介导的。 3）我们将测试DSCAM和DSCAML1调节正常发育细胞死亡的假设。长期目标：这项研究将揭示神经组织的基本方面，并为Fuerst博士提供了必要的资金，以建立以假设为驱动的生物医学研究的成功学术职业。意义：神经突化，细胞数的调节和躯体镶嵌间距是神经发育的基本方面，目前在脊椎动物的分子水平上尚不清楚。我们的初步研究表明，DSCAM在介导哺乳动物神经系统中的这些过程中起着至关重要的作用。识别DSCAM使用一系列小鼠突变等位基因和有条件等位基因的DSCAM功能的机制将有助于我们对神经系统发育的理解以及与神经失调相关的疾病的因果关系，并为神经科学界贡献有价值的研究模型。公共卫生相关性：拟议工作的主要目标是了解分子识别线索如何促进神经模式。研究将着重于发现两个识别线索的机制。唐氏综合征细胞粘附分子（DSCAM）及其同源DSCAM Like1（DSCAML1），介导视网膜内的电路形成。 DSCAM和DSCAML1都是神经层层压，神经突化和细胞数的调节所必需的。因此，了解这些分子功能将提高对多个方面神经发育的科学理解的机制。此外，降低DSCAM剂量会降低视网膜发育细胞死亡的发生率，这表明视网膜可能提供了一个极好的系统，以模拟唐氏综合症患者发生的神经元的增强神经元的发育性细胞死亡，这些患者因21染色体而过表达DSCAM。