Harnessing the therapeutic potential of neural crest cells by manipulating the primary cilium

摘要： 颅面畸形(CFAs)占先天缺陷的75%，是一种生物医学上的 每年在美国造成近7亿美元的负担。CFAs的外科修复 很困难，通常需要大量的骨骼组织来替换/重建面部 骷髅。用于修复CFA的骨移植经常不能整合，通常是同种异体移植 从中胚层衍生的骨。这是一个不太理想的组织来源，因为面部骨骼 胚胎起源于一种完全不同的称为神经脊细胞的细胞群 (NCCS)。然而，还没有在组织工程方法中使用，因为健壮的， 出生后的细胞来源不存在，它们的多能性引起了人们对 不受控制的分化。我的实验室的总体、长期目标是将我们的 了解NCC发生和发展的细胞、分子和生化机制 应用这些知识来产生新的治疗策略，以产生稳健的 NCC来源的组织，可用于颅面畸形的外科修复。至 为了实现这一目标，我们正专注于准确指导NCC的增殖和分化 通过操纵初级纤毛进入骨骼组织，初级纤毛是一种细胞器，其功能是 所有细胞的信号中枢。对初级纤毛是如何工作的有一个明确的理解 在NCC和其他细胞中传递分子信号，可能会发现几种新的治疗方法 疾病治疗的选择。我们工作的影响将是广泛和深远的 有可能彻底改变CFAs和纤毛疾病的治疗方式。

ABSTRACT: Craniofacial anomalies (CFAs) comprise 75% of congenital defects and represent a biomedical burden of almost 700 million dollars per year in the United States. Surgical repair of CFAs is difficult and often requires a large source of skeletal tissue to replace/reconstruct the facial skeleton. Bone grafts used to repair CFAs frequently fail to integrate and are commonly allografts from mesodermally derived bone. This is a suboptimal tissue source since the facial skeleton is embryonically derived from an entirely different population of cells called neural crest cells (NCCs). NCCs; however, have not been used in tissue engineering approaches because a robust, postnatal source of cells does not exist and their multipotent nature raises concerns of regarding uncontrolled differentiation. The over-arching, long-term goal of my laboratory is to integrate our understanding of the cellular, molecular and biochemical mechanisms of NCC development and apply this knowledge towards generating novel therapeutic strategies for generating a robust source of NCC-derived tissues amenable for the surgical repair of craniofacial anomalies. To achieve this goal, we are focusing on precisely directing NCCs proliferation and differentiation into skeletal tissue via manipulation of the primary cilia, the cellular organelle which functions as the signaling hub of all cells. Gaining a firm understanding of how the primary cilia work to transduce molecular signals in NCCs, and other cells, will likely identify several novel therapeutic options for disease treatment. The impact of our work would be broad and far-reaching as it has the potential to revolutionize how CFAs and ciliopathies are treated.