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

摘要： 颅面畸形（CFAs）占先天性缺陷的75%，是一种生物医学疾病。 在美国，每年有近7亿美元的负担。CFA的手术修复是 并且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的骨移植物经常不能整合，通常是同种异体移植物 中胚层来源的骨头这是一个次优的组织来源，因为面部骨骼是 从胚胎中衍生出来的一种完全不同的细胞群叫做神经嵴细胞 （净捐助国）。然而，NCC还没有用于组织工程方法， 出生后的细胞来源并不存在，它们的多能性引起了人们的关注， 不受控制的分化我的实验室的长期目标是整合我们的 了解NCC发展的细胞，分子和生化机制， 将这些知识应用于产生新的治疗策略，以产生稳健的 NCC衍生组织的来源，适用于颅面畸形的手术修复。到 为了实现这一目标，我们专注于精确地指导NCC的增殖和分化， 通过操纵初级纤毛进入骨骼组织，初级纤毛是细胞器， 所有细胞的信号中枢对初级纤毛如何工作有了深刻的理解， NCC和其他细胞中的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， 彻底改变CFA和纤毛病变治疗方式的潜力。

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.