Signaling Hierarchies in Vertebrate Development

许多遗传疾病的诊断和治疗因疾病症状的变化而受阻。这种变化的原因往往是未知的，因为没有进行系统的研究。本项目的目标是阐明正常表型恢复的机制，以及当这种机制在疾病状态下丧失时发生的不稳定性。我们假设变异可能是由于在发育过程中通常缓冲噪音的机制失效，例如基因活动和细胞读出的随机变异，从而确保健康儿童的表型稳定性。我们在三个项目中验证了这一假设，使用斑马鱼，一种由俄勒冈大学的这个小组首创的首要模式生物。这些项目利用斑马鱼的属性进行发育遗传学分析，包括对转基因标记鱼进行精细的延时显微镜观察，以实时跟踪发育事件和扰动，分析大分子复合物的形成，全基因组分析细胞信号事件，以及评估调节宿主基因表达的环境相互作用。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关注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表现出显著的变异程度。拟议的研究将探索上皮-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负责稳定性和弹性的基因。Project2测试了一个关于Usher综合征表型变异的新假设，Usher综合征是遗传性聋盲的最常见原因，该假设是由于Usher蛋白复合物的破坏导致细胞应激，导致随机细胞死亡。Project3研究巨结肠病的表型变异，巨结肠病是肠神经节病的主要原因，探索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运动缺陷来促进疾病进展。在四个核心单元的支持下，该项目将为三种特定疾病提供新的见解，并对疾病变异性的潜在机制产生新的认识，从而促进更好的疾病诊断和治疗。

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.