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

• 批准号: 8527784
• 负责人: PETER Gerard FUERST
• 金额: $ 22.48万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 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/8527784
• 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; receptor; relating to nervous system; research study; retinal rods

ABSTRACT: 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.

摘要：候选人与环境：彼得·富斯特（Peter Fuerst）博士将进行其中包含的研究 华盛顿州立大学的建议。华盛顿州立大学是一个理想的环境 使用小鼠模型进行先进的生物医学研究，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识别分子机制 基于视网膜的发展。所有由申请人开发的鼠标模型包括 唐氏综合征细胞粘附分子，DSCAM以及一系列等位基因小鼠的条件等位基因 DSCAM同源物DSCAM Like1（DSCAML1）的突变DSCAM菌株和无效等位基因。 DSCAM和DSCAM- 类似1对于神经系统的正常发育至关重要，并建议DSCAM有助于 唐氏综合症的病理学。在视网膜中，soma镶嵌间距需要DSCAM，调节细胞 数量和神经突植物和层压。我们有关DSCAM和DSCAML1的已发表的结果是 发现的突变的第一个证明是为了消融镶嵌图案和证明介导的第一个基因 脊椎动物中的以及异神经元排斥。具体目的：我们建议使用DSCAM和 DSCAML1突变小鼠模型，以发现视网膜开发和探测的机制 DSCAM在哺乳动物神经系统中的功能。这将通过测试以下来实现 该研究建议中详细介绍的假设。假设：1）我们将检验DSCAM的假设 使用等位基因序列和DSCAM小鼠突变线的条件等位基因介导多个不同的功能 从遗传和时间上分离DSCAM依赖性发育过程。 2）我们将测试 DSCAM介导细胞类型和抑制性细胞类型中的粘附的假设，并且 视网膜中的DSCAM活性是由均电相互作用而不是配体受体机制介导的 通过使用条件等位基因耦合到细胞类型特定的缺失。 3）我们将检验DSCAM的假设 DSCAML1调节正常发育细胞死亡。长期目标：这项研究将发现 神经组织的基本方面，并提供了福斯特博士建立一个必要的资金 成功的学术职业专注于假设驱动的生物医学研究。 显着性：神经突化，细胞数的调节和SOMA镶嵌间距是 神经发育的基本方面，目前在分子水平上尚不清楚 脊椎动物。我们的初步研究表明，DSCAM在调解这些过程中起着至关重要的作用 哺乳动物神经系统。识别DSCAM使用一系列鼠标发挥功能的机制 突变等位基因和有条件的等位基因将有助于我们对神经系统发展的理解和 与神经失调相关的疾病的因果关系，也为有价值的研究模型贡献 神经科学社区。