Genome Wide Association Study of Stochastic Cell Fate Determination In Drosophila

果蝇随机细胞命运决定的全基因组关联研究

• 批准号: 8824157
• 负责人: STEVEN G BRITT
• 金额: $ 23.26万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824157
• 关键词: ARNT protein; Aryl Hydrocarbon Receptor; Cell Lineage; Cells; Color; Complex; Data; Defect; Development; Disease; Drosophila genus; Eye; Eye Abnormalities; Eye Development; Genes; Genetic; Genetic Polymorphism; Genetic screening method; Goals; Human; Inbreeding; Individual; Knowledge; Laboratories; Mechanics; Mission; Modeling; Opsin; Organism; Outcome; Pathogenesis; Pathway interactions; Pattern; Photoreceptors; Play; Process; Proteins; Public Health; Quantitative Genetics; Quantitative Trait Loci; Research; Retina; Retinal; Retinal Pigments; Role; Signal Transduction; Specific qualifier value; Stochastic Processes; System; Testing; To specify; Vision Disorders; Visual system structure; Work; absorption; aryl hydrocarbons; base; cell type; disability; fly; genetic approach; genome wide association study; innovation; malformation; mutant; network models; new technology; public health relevance; trait

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.

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形成方面存在根本性差距。这个缺口的持续存在代表了视网膜发育中的一个重要问题，因为在它被填补之前，对正常和病理性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。该特定应用的目的是鉴定参与调节细胞凋亡的其他基因。 R7感光细胞命运的随机确定，以努力开发一个连贯的基因网络，将无脊椎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的规范Rh 3和Rh 4表达R7感光细胞，包括无刺，探戈，以及其他身份不明的基因。该假设是根据申请人实验室产生的初步数据形成的。这项研究的基本原理是观察到表达一种视觉色素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，该网络中的基因，产生这些不同的感光细胞类型，可以使用定量遗传方法进行鉴定和表征。在这些强有力的初步数据的指导下，这一假设将通过追求两个具体目标来检验：1）鉴定调节R7感光细胞的数量性状基因座 命运和视蛋白表达;和2）基于这些数量性状基因座开发和测试基因网络模型。根据第一个目标，一个成熟的定量遗传学方法将被应用于检查的规格Rh 3和Rh 4表达R7感光细胞。在第二个目标下，将鉴定的基因组装成网络模型，并测试它们调节R7感光细胞亚型特化的能力。这种方法是创新的，因为它使用新技术来检查视网膜发育的机制，这种方式以前没有进行过，因为这种方法很可能提供一种信息，有望从根本上改变我们对眼睛和视网膜发育的理解。这项研究意义重大，因为它有望垂直推进并扩展对视网膜如何形成和发展的理解。最终，这些知识有可能影响对先天性眼部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治疗方法的开发。