The role of continuous phenotypic variation in structural defects of the face

描述(申请人提供)：表型变异是头面部出生缺陷的一个标志，但了解变异形态和疾病之间的关系仍然难以捉摸。定义不同形态的基础是困难的，因为影响面部形态的遗传因素很多。然而，调节脸型的分子途径可能会汇聚在一组较小的细胞过程上。在这项工作中，我们专注于控制面部原基生长的两个细胞过程，因为生长的差异导致表型的差异。我们假设，通过离散地改变调节上颌主轴模式的分子信号通路，将产生连续的表型变异，这是由于最终控制细胞增殖和凋亡的基因表达模式的改变。在每个目标中，我们将重点研究细胞增殖、特定分子途径的信号传递和形态之间的关系。在第三个具体目标中，我们将把注意力转向研究细胞死亡、细胞存活、信号和形态之间的关系。在目标1中，我们将干扰大脑中控制神经脊细胞增殖的信号。在目标2中，我们将干扰调节细胞增殖的神经脊间充质内的信号。在目标3中，我们将干扰来自大脑和神经脊内调节细胞凋亡和细胞增殖的信号。在每个目标中，我们将使用三维和二维形态计量学来量化大脑和面部的形态变化，并将这些变化与特定分子通路的激活、控制细胞增殖和生存的信号分子、受体和转录因子的表达以及细胞增殖和细胞死亡相关联。在每个目标中，我们建议进行生化或基于细胞的实验，以改善由我们的处理引起的表型变化，并直接测试产生改变形态的机制。这些实验将使用形态计量分析进行评估，因为这种方法使我们能够客观和系统地评估我们的干预措施。总体而言，这项工作将使我们能够定量地评估生长在面部发育过程中形态变异产生中的作用。这种方法将使研究人员能够将特定基因中断的工作与调节面部形状的分子变化和细胞过程联系起来。此外，随着宫内高分辨率成像方法的出现，我们的研究将为开发能够更早检测面部畸形的参数奠定基础，并可能引领宫内治疗的道路。 与公共卫生相关：面部结构畸形很常见，通常表现出很大程度的形态变异；然而，变异背后的机制尚不清楚。我们的目标是检查影响生长的细胞过程，以评估正常和疾病人群中的形态变异。这项基础研究将有助于开发更好的宫内诊断和最终治疗面部结构性出生缺陷的指标。

DESCRIPTION (provided by applicant): Phenotypic variation is a hallmark of craniofacial birth defects, but understanding the relationship between variable morphology and disease remains elusive. The difficulty in defining the basis for variable morphology occurs because of the multitude of genetic factors that influence facial morphology. However, the molecular pathways that regulate facial form are likely to converge on a smaller set of cellular processes. In this work, we focus on two cellular processes that control growth of the facial primordia, because differences in growth contribute to variation in phenotype. We hypothesize that by discretely altering molecular signaling pathways that regulate patterning of the major axes of the upper jaw continuous phenotypic variation will be produced due to altered patterns of gene expression that ultimately control cell proliferation and apoptosis. In each Aim we will focus on the relationship among cell proliferation, signaling by specific molecular pathways, and morphology. In the Third Specific Aim we will turn our attention to examine the relationship among cell death, cell survival, signaling, and morphology. In Aim 1 we will disrupt signals form the brain that control proliferation of neural crest cells. In Aim 2 we will disrupt signals within the neural crest mesenchyme that regulate cell proliferation. In Aim 3 we will disrupt signals from the brain and within the neural crest that regulate apopotosis and cell proliferation. In each Aim we will use 3-D and 2-D morphometrics to quantify morphologic changes in the brain and face, and we will correlate these changes with activation of specific molecular pathways, expression of signaling molecules, receptors, and transcription factors that control cell proliferation and survival, and cell proliferation and cell death. In each aim, we propose biochemical or cell- based experiments to ameliorate the phenotypic changes induced by our treatments and directly test the mechanisms that underlie production of altered morphology. These experiments will be evaluated using morphometric analysis, because this approach allows us to objectively and systematically evaluate our interventions. Overall, this work will allow us to quantitatively assess the role of growth in production of morphologic variation during development of the face. This approach will allow investigators to bridge work on specific genetic disruptions with molecular changes and cellular processes that regulate facial form. Further, with the advent of high resolution in utero imaging methods, our research will create a basis for developing parameters that allow earlier detection of facial malformations and may lead the way to in utero treatments. PUBLIC HEALTH RELEVANCE: Structural malformations of the face are common and often exhibit a large degree of morphologic variation; however, the mechanisms underlying variation are not known. Our objective is to examine cellular processes that affect growth in order to assess morphologic variation in normal and diseased populations. This basic research will help develop metrics for better in utero diagnostics and eventual treatments of structural birth defects of the face.