Cell Biological Determinants of Jaw Size

描述（由申请人提供）：下颌长度的正确建立对喂养、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，是一种下颌尺寸不足的情况。颅面缺陷如小颌畸形的治疗通常涉及多种手术干预，这是一个漫长，昂贵，情感和身体消耗的过程。因此，预防为高危人群提供了一个受欢迎的选择。然而，确定潜在的拯救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，连同大部分颅面骨骼，起源于神经嵴（NC），这是一个短暂的，多能的细胞群，出现在神经板的边界。颌骨的大小可能与NC祖先种群的大小（即数量）直接相关。至少有三个参数可能导致NC数量的变化：指定为NC前体的细胞数量（与神经上皮或外胚层前体相反），NC细胞死亡率和NC增殖率。事实上，一些研究表明，由于NC增殖减少或NC死亡增加，小颌畸形与NC数量的变化密切相关。我们的初步分析表明，颌骨大小的物种特异性差异出现在发育过程中，可能与NC数的差异有关。我们假设神经嵴细胞的数量调节颌骨大小，而颌骨大小的物种特异性差异源于NC前体数量、NC存活率和/或NC增殖率的进化变化。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，并评估这些处理对颌骨大小的影响。我们的建议有三个具体的目标，集中在下颌骨骨架和研究可能有助于颌骨尺寸的三个参数的作用。特异性Aim 1将确定指定为NC前体的细胞数量是否调节颌骨大小。特异性目标2将确定NC的生存差异是否会导致颌骨大小的差异。最后，特异性Aim 3将确定NC的增殖率是否调节颌骨大小。结果将在分子、细胞、组织学和形态学水平上进行分析。该项目意义重大，因为了解调节颌骨大小的发育机制将有助于建立基于生物学的预防疗法。

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.