Signaling Hierarchies in Vertebrate Development

描述（由申请人提供）：许多遗传性疾病的诊断和治疗受到疾病症状变化的阻碍。这种差异的原因往往是未知的，因为没有进行系统的研究。这个项目的目标是阐明正常表型恢复力的机制，以及当这些机制在疾病状态下丢失时发生的不稳定性。我们假设，变异可能是由于发育过程中通常缓冲噪音的机制失效所致，例如基因活性和细胞读数的随机变异，从而确保健康儿童的表型稳定性。我们在三个项目（项目）中测试这一假设，使用斑马鱼，这是由俄勒冈州大学的这个小组开创的一种首要模式生物。这些项目利用斑马鱼的属性进行发育遗传学分析，包括对转基因标记的鱼进行精密的延时显微镜检查，以跟踪真实的时间内的发育事件和扰动，大分子复合物形成的测定，细胞信号事件的全基因组分析，以及调节宿主基因表达的环境相互作用的评估。这些研究将阐明导致疾病症状变异性的事件的性质。项目1的重点是弗雷泽综合征的变异，这是一种罕见的遗传性疾病，其特征是颅面和咽上皮破坏，在受影响的个体之间以及同一个体的左右两侧都显示出显着程度的变异。拟议的研究将探讨上皮-间充质相互作用的失败如何导致颅面骨骼发育的差异，并将揭示在正常条件下观察到的稳定性和弹性的基因。项目2测试了Usher综合征表型变异的新假设，Usher综合征是遗传性眼盲的最常见原因，假设它是由Usher蛋白复合物的破坏引起的，Usher蛋白复合物引起细胞应激，导致随机细胞死亡。项目3研究了与先天性巨结肠相关的表型变异，先天性巨结肠是肠道无神经节细胞症的主要原因，探索了肠神经系统调节肠道细菌群落组成的假设，以及改变的群落通过促进炎症和放大肠道动力缺陷而促进疾病进展的假设。在四个核心单位的支持下，该计划项目将提供对三种特定疾病的新见解，并对疾病变异性的机制有新的认识，这将促进更好的疾病诊断和治疗。

DESCRIPTION (provided by applicant): Diagnosis and treatment of many genetic diseases is hindered by variation in disease symptoms. The reasons for this variation are often unknown because systematic studies have not been undertaken. The goal of this Program Project is to elucidate mechanisms underlying normal phenotypic resilience and the instability that occurs when such mechanisms are lost in the disease state. We hypothesize that variation can result from failure of mechanisms that normally buffer against noise in developmental processes, for example stochastic variation in gene activities and cellular read-outs, and thus assure phenotypic stability in healthy children. We test this hypothesis in three Projects (Projects), using the zebrafish, a premiere model organism pioneered by this group at the University of Oregon. The projects take advantage of attributes of the zebrafish for developmental genetics analyses, including exquisite time-lapse microscopy of transgenically labeled fish to follow developmental events and perturbations in real time, assays of macromolecular complex formation, genome-wide analyses of cell signaling events, and assessment of environmental interactions that modulate host gene expression. These studies will elucidate the nature of events leading to variability in disease symptoms. Project1 focuses on variation In Fraser syndrome, a rare inherited disorder characterized by craniofacial and pharyngeal epithelial disruptions that show a remarkable degree of variation, both among affected individuals and on the left and right sides of the same individual. Proposed studies will explore how failure of epithelial-mesenchymal interactions results in differences in craniofacial skeletal development and will reveal genes responsible for the stability and resilience seen under normal conditions. Project2 tests a novel hypothesis for phenotypic variation with Usher syndrome, the most prevalent cause of hereditary deaf-blindness, hypothesizing that it results from disruption of complexes of Usher proteins that cause cellular stress that leads to stochastic cell death. Project3 investigates phenotypic variation associated with Hirschsprung disease, the leading cause of intestinal aganglionosis, exploring the hypothesis that the enteric nervous system regulates composition of intestinal bacterial communities and that altered communities contribute to disease progression by promoting inflammation and amplifying intestinal motility defects. Together with support of four Core Units, this Program Project will provide novel insights into three specific diseases and develop a new understanding of the mechanisms underlying disease variability that will promote better disease diagnosis and treatment.