Genome Wide Association Study of Stochastic Cell Fate Determination In Drosophila

描述(由申请人提供)：在理解随机细胞命运决定如何调节视网膜马赛克的形成方面有一个根本的空白。这种缝隙的持续存在代表了视网膜发育中的一个重要问题，因为在它被填充之前，对正常和病理眼睛发育的理解将仍然是支离破碎和不完整的；长期目标是了解不同类别的光感受器是如何由个体光感受器固有的随机机制指定的。这一特殊应用的目标是识别参与调节 随机确定R7光感受器细胞的命运，以努力开发一个连贯的基因网络，将无刺和探戈的功能整合到一个全面的可测试模型中。中心假设是，一个复杂的基因网络控制着表达R7光感受器细胞的Rh3和Rh4的规格，其中包括无刺、探戈和其他未知基因。这一假设是基于申请人实验室提供的初步数据而形成的。这项拟议研究的基本原理是观察到，表达一种或另一种视觉色素的R7光感受器的比例是一个连续可变的数量性状。这表明，这个网络中产生这些不同光感受器细胞类型的基因可以使用定量遗传学方法进行识别和表征。在这个强大的初步数据的指导下，这一假说将通过追求两个具体目标来检验：1)识别调节R7感光细胞的数量性状基因座 2)建立和检验基于这些数量性状基因座的基因网络模型。在第一个目标下，一种成熟的数量遗传学方法将被应用于检测表达R7光感受器细胞的Rh3和Rh4的规格。在第二个目标下，识别出的基因将被组装成一个网络模型，并测试它们调节R7光感受器细胞亚型规格的能力。这种方法是创新的，因为它使用了新技术来研究视网膜发育的机制，这是以前从未采用过的方式，而且这种方法很可能提供一种有望从根本上改变我们对眼睛和视网膜发育的理解的信息。这项拟议的研究意义重大，因为它有望在纵向上推进和扩大对视网膜如何形成和发展的理解。最终，这些知识可能会影响对先天性眼睛缺陷和畸形的理解和治疗，并通过操纵视网膜内的特定细胞来影响视觉系统疾病的新疗法的开发。

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding how stochastic cell fate determination regulates the formation of the retinal mosaic. Continued existence of this gap represents an important problem in retinal development because, until it is filled, the understanding of normal and pathological eye development will remain fragmented and incomplete; The long-term goal is to understand how different classes of photoreceptors are specified by stochastic mechanisms that are intrinsic to an individual photoreceptor. The objective in this particular application is to identify additional genes involved in regulating the stochastic determination of R7 photoreceptor cell fate in an effort to develop a coherent gene network that integrates the function of spineless and tango into a comprehensive testable model. The central hypothesis is that a complex gene network controls the specification of Rh3 and Rh4 expressing R7 photoreceptor cells that includes spineless, tango, as well as additional unidentified genes. This hypothesis has been formed based on preliminary data produced in the applicant's laboratory. The rationale for the proposed research is the observation that the proportion of R7 photoreceptors that express one visual pigment or another is a continuously variable quantitative trait. This suggests that the genes within this network, which produces these different photoreceptor cell types, can be identified and characterized using quantitative genetic approaches. Guided by this strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify Quantitative Trait Loci that regulate R7 photoreceptor cell fate and opsin expression; and 2) Develop and test a gene network model based on these Quantitative Trait Loci. Under the first aim, a proven quantitative genetics approach will be applied to examine the specification of Rh3 and Rh4 expressing R7 photoreceptor cells. Under the second aim, the identified genes will be assembled into a network model and tested for their ability to regulate R7 photoreceptor cell subtype specification. The approach is innovative, because it uses new technologies to examine the mechanics of retinal development in a way that has not been previously undertaken and because this approach is likely to provide a type of information that promises to fundamentally alter our understanding of eye and retina development. The proposed research is significant, because it is expected to vertically advance and expand the understanding of how the retina is formed and develops. Ultimately, such knowledge has the potential to impact the understanding and treatment of congenital eye defects and malformations and influence the development of new treatments for visual system diseases through the manipulation of specific cells within the retina.