Cell Biological Determinants of Jaw Size

描述（由申请人提供）：正确建立颌骨长度对进食、呼吸和口腔运动技能的正常发展至关重要。小颌畸形，也被称为下颌发育不全，是一种下颌尺寸过小的情况。颅面缺陷如小颌畸形的治疗通常涉及多次手术干预，这是一个漫长，昂贵，情绪和身体排水的过程。因此，预防为面临风险的个人提供了一个受欢迎的替代办法。然而，确定潜在的救援或再生策略取决于对调节颌骨大小的发育过程的理解。颌骨与大部分颅面骨骼沿着来源于神经嵴（NC），神经嵴是一种短暂的多能细胞群，产生于神经板的边缘。颌的大小可能与祖先群体的大小直接相关（即，数）的NC。至少有三个参数可能导致NC数量的变化：指定为NC前体（与神经上皮或外胚层前体相反）的细胞数量、NC细胞死亡率和NC增殖率。事实上，一些研究已经将小颌畸形与NC数量的变化密切相关，这是由于NC增殖减少或NC死亡增加。我们的初步分析表明，种属特异性差异的颌骨大小出现在发展过程中，可能与NC数的差异。我们假设，神经嵴细胞的数量调节颌骨大小和物种特异性的差异，颌骨大小的进化变化产生的NC前体的数量，NC的生存率和/或NC增殖率。为了验证我们的假设，我们将操纵NC前体的数量，调节NC细胞死亡，改变NC增殖，并评估这些治疗对颌骨大小的影响。我们的建议有三个具体目标，重点是下颌骨骼和调查的作用，三个参数可能有助于颌骨大小。具体目标1将确定指定为NC前体的细胞数量是否调节钳口尺寸。具体目标2将确定NC存活率的差异是否会导致钳口尺寸的差异。最后，具体目标3将确定NC的增殖率是否调节颌骨大小。将在分子、细胞、组织学和形态学水平上分析结果。这个项目是重要的，因为了解发育机制调节颌骨大小将有助于建立基于生物学的预防性治疗。

DESCRIPTION (provided by applicant): Proper establishment of jaw length is essential to feeding, breathing, and normal development of oral-motor skills. Micrognathia, also referred to as mandibular hypoplasia, is a condition where the jaw is undersized. Treatment for craniofacial defects such as micrognathia often involves multiple surgical interventions, a lengthy, costly, and emotionally and physically draining process. Prevention, therefore, provides a welcome alternative for at-risk individuals. Identifying potential strategies for rescue or regeneration depends, however, on an understanding of the developmental processes regulating jaw size. The jaw, along with most of the craniofacial skeleton, derives from the neural crest (NC), which is a transient, multi-potent cell population that arises at the border of the neural plate. The size of jaws may be directly linked to the size of the progenitor population (i.e., number) of NC. At least three parameters are likely to contribute to variation in NC number: the number of cells that are specified as NC precursors (as opposed to neuroepithelial or ectodermal precursors), the rate of NC cell death, and the rate of NC proliferation. In fact, several studies have closely associated micrognathia with a change in NC number as a result of decreased NC proliferation or increased NC death. Our preliminary analyses indicate that species-specific differences in jaw size arise during development and may be associated with differences in NC number. We hypothesize that the number of neural crest cells regulates jaw size and that species-specific differences in jaw size arise from evolutionary changes in the number of NC precursors, the rate of NC survival and/or the rate of NC proliferation. To test our hypothesis, we will manipulate the number of NC precursors, modulate NC cell death, alter NC proliferation, and assess the effect of these treatments on jaw size. Our proposal has three Specific Aims, focusing on the lower jaw skeleton and investigating the role of three parameters likely to contribute to jaw size. Specific Aim 1 will determine if the number of cells specified as NC precursors regulates jaw size. Specific Aim 2 will determine if differences in survival of NC contribute to differences in jaw size. Finally, Specific Aim 3 will determine if proliferation rates of NC regulate jaw size. Results will be analyzed on molecular, cellular, histological and morphological levels. This project is significant because an understanding of developmental mechanisms regulating jaw size will contribute to the establishment of biologically based preventative therapies.