Elucidating signaling networks in Anterior Segment development, repair and diseases

眼前节（AS）组织的缺陷导致一组高度衰弱的眼部疾病，称为前房性眼病。 节段发育不全（ASD）。ASD是先天性角膜混浊的主要原因之一，并导致青光眼 在约50%的病例中，并且通常与近视相关。尽管很少有致病基因被发现， 这类疾病中组织畸形的分子和细胞机制。几 包括Meckel、Bardet Biedl和Joubert综合征的纤毛病显示影响AS组织的病症，包括 严重近视。我们最近报道，条件性切除神经嵴细胞（NCC）的初级纤毛导致 在与人类相似的条件下，在小鼠模型中观察到ASD。我们已经证明，初级纤毛的 神经嵴来源的POM介导Hedgehog（Hh）途径。然而，我们的初步结果表明， 可能在AS形态发生和修复中以组织特异性方式发挥重要作用。的目的 拟议的研究是阐明在细胞周期中纤毛蛋白所协调的信号通路和细胞机制。 角膜和其他AS结构的形态发生。具体来说，我们将测试我们的核心工作假设，主要 纤毛使POM的神经嵴衍生细胞能够解释局部形态发生线索并引起不同的细胞行为 在AS的不同结构的形态发生和修复过程中。为了验证这一假设，我们已经产生了特定的遗传 和计算工具，并开发了一种体内成像方法，这将使我们能够a）阐明重叠， 初级纤毛和Hh通路在AS组织的发育和修复过程中的不同作用; B）鉴定信号传导 与AS形态发生相关的初级纤毛下游网络，以及c）进行以下功能表征： 具有软骨形成能力的pNC谱系的新型纤毛依赖性细胞群。总的来说， 这项工作将揭示初级纤毛信号传导的整合作用，这是实现正常AS形态发生所必需的。重要的是， 对纤毛相关信号级联的描述将有助于确定治疗ASD的新治疗策略 和创伤

Defects of the anterior segment (AS) tissue lead to a group of highly debilitating eye disorders referred to as Anterior Segment Dysgenesis (ASD). ASD represents one of the leading causes of congenital corneal opacity and leads to glaucoma in ~50% of the cases and are often associated with myopia. Although few causative genes have been identified, little is known about the molecular and cellular mechanisms underlying tissue malformation in this class of diseases. Several ciliopathies including Meckel, Bardet Biedl, and Joubert syndromes display conditions affecting tissues of the AS including severe myopia. We have recently reported that conditional ablation of the primary cilium in neural crest cells (NCC) leads to ASD in the mouse model with conditions similar to those observed in humans. We have shown that primary cilia of the neural crest derived POM mediate the Hedgehog (Hh) pathway. However, our preliminary results suggest that the cilium could play distinct roles in a tissue specific manner important for AS morphogenesis and repair. The objective of the proposed study is to elucidate the signaling pathways and cellular mechanisms orchestrated by ciliary proteins during morphogenesis of the cornea and other AS structures. Specifically, we will test our central working hypothesis that primary cilia enable neural crest-derived cells of the POM to interpret local morphogenetic cues and elicit distinct cellular behaviors during morphogenesis and repair of different structures of the AS. To test this hypothesis, we have generated specific genetic and computational tools and developed an in vivo imaging approach that will allow us to a) elucidate overlapping and distinct roles of primary cilia and the Hh pathway during the development and repair of AS tissues; b) To identify signaling networks downstream of the primary cilium relevant for AS morphogenesis, and c) conduct a functional characterization of a novel cilia-dependent cell population of the pNC lineage with chondrogenic capabilities. Collectively, the outcome of this work will reveal the integrative role of primary cilia signaling necessary to achieve normal AS morphogenesis. Importantly, delineation of the cilia-related signaling cascades will enable the identification of new therapeutic strategies to treat ASD and trauma.