Development of Retinal Bipolar Cells

视网膜双极细胞的发育

• 批准号: 8009427
• 负责人: BENJAMIN E REESE
• 金额: $ 35.71万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009427
• 关键词: Alleles; Apoptosis; Architecture; Breeding; Candidate Disease Gene; Cell Count; Cell Death; Cell Density; Cell Survival; Cells; Cellular Morphology; Communities; Data; Databases; Dendrites; Dependency; Detection; Development; Developmental Gene; Event; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genomics; Haplotypes; Harvest; Inbred Strains Mice; Individual; Inherited; Inner Nuclear Layer; Investigation; Knock-out; Knockout Mice; Label; Laboratories; Maps; Messenger RNA; Microarray Analysis; Molecular Genetics; Morphogenesis; Morphology; Mouse Strains; Mus; Mutant Strains Mice; Neurons; Output; Pattern; Photoreceptors; Play; Population; Predisposition; Process; Production; Quantitative Trait Loci; Recombinant Inbred Strain; Relative (related person); Replacement Therapy; Research; Research Proposals; Resources; Retina; Retinal; Retinal Cone; Retinal Diseases; Role; Signal Transduction; Source; System; Testing; Transcript; Variant; cell type; consomic; density; gene function; horizontal cell; nerve supply; outer plexiform layer; programs; public health relevance; relating to nervous system; research study; retinal rods

DESCRIPTION (provided by applicant): The cellular architecture and connectivity of the vertebrate retina is remarkably conserved across species. What distinguishes these retinas most is the relative numbers of each of the different cell types. Even within a species, there is significant variation in the size of neuronal populations. Polymorphic genes controlling the processes regulating cellular production, fate assignment and survival contribute most of this variation between individuals, and the present investigation will seek to identify genes responsible for this variation, and to understand their role in those processes modulating proliferation, fate determination and apoptosis. Twenty-six recombinant inbred strains of mice derived from the A/J and C57BL/6J strains of mice will be used to determine the natural variation in four different types of retinal bipolar cell, and the degree of co-variation between cell types will be examined. The variation in bipolar cell number will also be compared with data for cone photoreceptor number and with new data collected for rod photoreceptors. Variation in cell number will be mapped to genomic loci where candidate polymorphic genes will be identified and tested using gene knock-out strategies. The role of cell death in establishing bipolar cell numbers, and its temporal occurrence, will be assessed directly in Bax knock-out mice, while its afferent-dependency will be defined in coneless and conefull mutant mice. Other cell types have been shown to have their morphological differentiation controlled by the density of neighboring like-type cells as well as by their afferents, and so each of these variables will be modulated to determine their effects upon the differentiation of bipolar cell dendrites. Finally, a developmental transcriptome analysis of the retina will be conducted in these each of these recombinant inbred strains, and made available to the scientific community on-line at NerveNetwork. This will enable the direct mapping of variations in gene expression to genomic loci, thereby aiding in the identification of candidate genes underlying the above variations in bipolar and photoreceptor cell number, and the detection of correlations in gene expression to identify regulatory networks that participate in the production of individual types of bipolar or photoreceptor cells. These experiments will reveal the determinants of nerve cell number and morphology, clarifying our understanding of retinal development, as well as identifying gene polymorphisms that may contribute to retinal disease. PUBLIC HEALTH RELEVANCE: This research program will identify the molecular and genetic determinants controlling the natural variation in nerve cell number, examining the populations of photoreceptors and bipolar cells. It will determine how this variation in afferent and target cell number modulates the dendritic morphology of the bipolar cell. It will, consequently, clarify the developmental events and their underlying mechanisms that produce the functional architecture and connectivity of the retina. These studies will contribute to our understanding of retinal development and degeneration, and will enlighten our approach in developing treatments for retinal disease, particularly where the latter seek to re- establish connectivity following cell replacement therapy.

描述(申请人提供)：脊椎动物视网膜的细胞结构和连通性在不同物种之间非常保守。这些视网膜的最大区别是每种不同细胞类型的相对数量。即使在一个物种内部，神经元种群的大小也存在显著差异。控制细胞生产、命运分配和生存的过程的多态基因是这种个体之间差异的主要原因，本研究将试图找出导致这种差异的基因，并了解它们在调控增殖、命运决定和凋亡的过程中的作用。来自A/J和C57BL/6J品系的26个重组近交系小鼠将被用来确定四种不同类型的视网膜双极细胞的自然变异，并将检查细胞类型之间的协变程度。双极细胞数量的变化也将与视锥感光细胞数量的数据和杆状感光细胞收集的新数据进行比较。细胞数量的变化将被映射到基因组位置，在那里将使用基因敲除策略识别和测试候选的多态基因。在Bax基因敲除小鼠中，将直接评估细胞死亡在建立双极细胞数量中的作用及其在时间上的出现，而其传入依赖性将在无锥体和锥体突变小鼠中定义。其他类型的细胞的形态分化受相邻类细胞的密度和它们的传入细胞的控制，因此这些变量中的每一个都将被调节以确定它们对双极细胞树突分化的影响。最后，将在这些重组近交系中对视网膜进行发育转录组分析，并在NerveNetwork上提供给科学界。这将使基因表达的变异直接定位到基因组位置，从而有助于识别导致上述双极细胞和感光细胞数量变化的候选基因，并检测基因表达的相关性，以识别参与产生特定类型的双极细胞或感光细胞的调控网络。这些实验将揭示神经细胞数量和形态的决定因素，澄清我们对视网膜发育的理解，以及识别可能导致视网膜疾病的基因多态。 公共卫生相关性：该研究计划将确定控制神经细胞数量自然变化的分子和遗传决定因素，检查光感受器和双极细胞的数量。它将确定传入细胞和靶细胞数量的这种变化如何调节双极细胞的树突形态。因此，它将阐明产生视网膜功能结构和连接性的发育事件及其潜在机制。这些研究将有助于我们了解视网膜的发育和退化，并将启发我们开发视网膜疾病的治疗方法，特别是在后者寻求在细胞替代治疗后重新建立连接的情况下。