Neuronogenesis in the Non-pigmented Retina

描述（由申请人提供）：在视网膜色素上皮细胞中缺乏色素的哺乳动物，包括人类，具有许多视网膜和视觉系统异常。 类似的异常发生在白化病人，缺乏色素在整个身体，包括眼睛和眼白化病缺乏色素只在眼睛。 我们建议，缺乏色素影响细胞增殖的神经视网膜的发展早期，这些异常的细胞增殖影响细胞数量和细胞类在成人视网膜。 我们描述了一组假设的行为的视网膜细胞的色素与非色素的眼睛，然后提出具体的实验来测试这一假设。 对于本项目，将使用具有两种不同类型的非色素视网膜的小鼠：C57 BL/6 J-tyrc 2 J/tyrc 2 J（白化病）和Oa 1 tm 1 Inc/Y（眼白化病）。这些小鼠在色素加工途径的不同位置有突变，两者的表型与人类基本相似。Oa 1 tmInc小鼠是人Oa 1的鼠同系物（也称为Nettleship-Falls型眼白化病）。我们将使用的有色小鼠被选择为具有与非有色小鼠相同的遗传背景。该项目有3个具体目标，将在高空间和时间分辨率下进行研究：1）细胞周期，2）离开与留在细胞周期中的子细胞的比例，以及3）特定视网膜类细胞的生成。 我们将实现高的空间和时间分辨率为这个项目使用本实验室开发的方法，利用双标记与两个S期标记，溴脱氧尿苷和氚标记的胸苷。 所获得的结果将告诉我们色素和非色素动物在发育中的视网膜中细胞产生的最早差异，包括有关视网膜内区域差异的信息。 这些详细的信息对于理解视网膜色素缺乏如何产生异常以及治疗和疗法的合理发展非常重要。

DESCRIPTION (provided by applicant): Mammals, including humans, lacking pigment in the retinal pigment epithelial cells have a number of abnormalities of the retina and visual system. Similar abnormalities occur in albinos that lack pigment in the entire body including the eye and in ocular albinos that lack pigment only in the eye. We propose that the lack of pigment affects cell proliferation early in the development of the neural retina and that these abnormalities in cell proliferation affect both cell number and cell class in the adult retina. We describe a hypothetical set of behaviors for the proliferating cells of the retina in pigmented vs non-pigmented eyes and then propose specific experiments to test this hypothesis. For this project mice with two different types of non-pigmented retinas will be used: C57BL/6J-tyrc2J/tyrc2J, which are albino, and Oa1tm1Inc/Y which are ocular albinos. These mice have mutations at different locations in the pigment processing pathway, and both have phenotypes that are substantially similar to their human counterparts. The Oa1tmInc mouse is a murine homolog of human Oa1 (also known as Nettleship-Falls Type Ocular Albinism). The pigmented mice that we will use are chosen to have the same genetic background as the non-pigmented mice. The project has 3 specific aims which will examine at high spatial and temporal resolution: 1) the cell cycle, 2) the proportion of daughter cells leaving vs remaining in the cell cycle, and 3) the generation of cells of specific retinal classes. We will achieve both high spatial and temporal resolution for this project using methods developed in this laboratory that exploit double labeling with two S-phase markers, bromodeoxyuridine and tritiated thymidine. The results obtained will tell us the earliest differences in the production of cells in the developing retina for pigmented and non-pigmented animals including information about regional differences within the retina. Such detailed information is important for understanding how the lack of retinal pigment produces abnormalities and for the rationale development of treatments and therapies.