Neuronogenesis in the Non-pigmented Retina

描述（由申请人提供）：哺乳动物，包括人类，视网膜色素上皮细胞缺乏色素，视网膜和视觉系统有许多异常。包括眼睛在内的全身缺乏色素的白化病患者和仅眼部缺乏色素的眼部白化病患者也会出现类似的异常。我们认为色素的缺乏会影响神经视网膜发育早期的细胞增殖，并且这些细胞增殖的异常会影响成年视网膜的细胞数量和细胞类别。我们描述了一组假设的行为视网膜细胞增殖的色素和非色素的眼睛，然后提出具体的实验来验证这一假设。本项目将使用两种不同类型的非色素视网膜小鼠：C57BL/6J-tyrc2J/tyrc2J是白化的，Oa1tm1Inc/Y是眼白化的。这些小鼠在色素加工途径的不同位置发生突变，并且两者的表型与人类的表型基本相似。Oa1tmInc小鼠是人类Oa1（也称为netttleship - falls型眼白化病）的小鼠同源物。我们将使用的有色素的老鼠与没有色素的老鼠有着相同的遗传背景。该项目有3个具体目标，将以高空间和时间分辨率进行研究：1)细胞周期，2)子细胞离开与留在细胞周期中的比例，3)特定视网膜类别细胞的产生。我们将利用实验室开发的方法，利用两种s相标记物，溴脱氧尿嘧啶和氚化胸腺嘧啶的双重标记，为这个项目实现高空间和时间分辨率。获得的结果将告诉我们色素动物和非色素动物视网膜发育中细胞产生的最早差异，包括视网膜内区域差异的信息。这些详细的信息对于了解视网膜色素缺乏如何产生异常以及治疗和治疗的基本原理发展非常重要。

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.