The Role of Neural Crest in Facial Patterning

描述（由申请人提供）： 我的长期职业目标是研究正常和异常面部发育的细胞和分子基础。我的研究将为产生基于生物学的治疗方法来治疗人类面部畸形提供基础。为了为我的职业生涯做准备，我接受了胚胎学、解剖学、发育分子生物学和颅面异常等多学科的培训。通过这种多样化的背景，我获得了研究复杂的细胞和分子机制的技能，这些机制形成了面部发育的模式。未来在理解正常和异常的面部形态发生方面的进展将来自于发现和实验性地操纵分子和细胞信号，这些信号形成头部的骨骼、肌肉、神经和血管系统。因此，为了对这一研究领域做出实质性贡献，我将工作重点放在细胞分化的调控上，这是颅面发育的重要组成部分。这一过程的中断会导致一系列人类出生缺陷。例如，颅缝前部的成骨细胞过早分化导致颅缝早闭。相反，中缘上皮分化延迟导致继发腭裂。因此，胚胎细胞的多个群体之间的分化的时间是正常的面部图案的先决条件。 神经嵴、外胚层和中胚层的颅群学习何时分化成离散的面部结构（如骨、表皮和肌肉）的细胞和分子机制尚不清楚。我推测，在发展中的脸，神经嵴细胞调节自己的时间分化，以及外胚层和中胚层。为了验证这一假设，我将在两种具有显著不同成熟率的鸟类之间进行一系列神经嵴移植，这将改变供体和宿主细胞群体之间传递的时间信息。使用各种形态学，细胞和分子的方法，我的分析将确定是否捐助者神经嵴衍生软骨和骨骼，以及主机衍生的表皮和肌肉结构的时间表上的捐助者，主机，或两者的组合。该项目在使用新方法研究面部生长调节方面具有重要意义，并将为出生缺陷提供有价值的见解。

DESCRIPTION (provided by applicant): My long-term career objective is to investigate the cellular and molecular bases for normal and abnormal facial development. My research will provide a foundation for generating biologically based therapies to treat facial malformations in humans. To prepare for my career, I have received multidisciplinary training in embryology, anatomy, developmental molecular biology, and craniofacial anomalies. Through this diverse background I have acquired skills for studying complex cellular and molecular mechanisms that pattern the developing face. Future progress in understanding normal and abnormal facial morphogenesis will come from discovering and experimentally manipulating molecular and cellular signals that pattern the skeletal, muscular, nervous, and vascular systems of the head. Therefore, in order to provide a substantial contribution to this area of research, I am focusing my work on the regulation of cell differentiation, which is an essential component of craniofacial development. Disruptions to this process result in a range of human birth defects. For example, premature cell differentiation within the osteogenic front of cranial sutures causes craniosynostoses. Conversely, a delay in differentiation of median edge epithelium leads to clefting of the secondary palate. Thus, the timing of differentiation among multiple populations of embryonic cells is a prerequisite for normal facial patterning. Cellular and molecular mechanisms through which cranial populations of neural crest, ectoderm, and mesoderm learn when to differentiate into discrete facial structures such as bone, epidermis, and muscle are unknown. I hypothesize that in the developing face, neural crest cells regulate their own temporal differentiation as well as that of ectoderm and mesoderm. To test this hypothesis, I will perform a series of neural crest transplants between two avian species that have significantly different maturation rates, which will alter temporal information being conveyed among populations of donor and host cells. Using a variety of morphological, cellular, and molecular approaches, my analyses will determine whether donor neural crest-derived cartilages and bones, as well as host-derived epidermal and muscular structures develop on a timetable of the donor, host, or a combination of both species. This project is significant in using a novel approach to investigate regulation of facial growth and will provide valuable insights on birth defects.