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

描述（由申请人提供）：表型变异是颅面出生缺陷的标志，但了解可变形态和疾病之间的关系仍然难以捉摸。由于影响面部形态的遗传因素众多，因此难以定义可变形态的基础。然而，调节面部形状的分子途径可能会集中在一组较小的细胞过程上。在这项工作中，我们专注于两个细胞过程，控制面部原基的生长，因为生长的差异有助于表型的变化。我们假设，通过离散地改变分子信号通路，调节图案的主要轴的上颌连续的表型变异将产生由于改变模式的基因表达，最终控制细胞增殖和凋亡。在每个目标中，我们将重点关注细胞增殖，特定分子途径的信号传导和形态学之间的关系。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，信号传导和形态之间的关系。在目标1中，我们将破坏来自大脑的控制神经嵴细胞增殖的信号。在目标2中，我们将破坏调节细胞增殖的神经嵴间充质内的信号。在目标3中，我们将干扰来自大脑和神经嵴内的信号，这些信号调节细胞凋亡和细胞增殖。在每个目标中，我们将使用3-D和2-D形态测量来量化大脑和面部的形态变化，我们将这些变化与特定分子通路的激活，信号分子，受体和转录因子的表达相关，这些因子控制细胞增殖和存活，以及细胞增殖和细胞死亡。在每一个目标中，我们提出了生物化学或基于细胞的实验来改善由我们的治疗诱导的表型变化，并直接测试产生改变的形态的机制。这些实验将使用形态测量分析进行评估，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。总的来说，这项工作将使我们能够定量评估的作用，在生产的形态变化的发展过程中的脸。这种方法将使研究人员能够将特定的遗传破坏与调节面部形状的分子变化和细胞过程联系起来。此外，随着子宫内高分辨率成像方法的出现，我们的研究将为开发参数奠定基础，这些参数允许早期检测面部畸形，并可能导致子宫内治疗。 公共卫生相关性：面部的结构畸形是常见的，并且经常表现出很大程度的形态学变化;然而，变化的机制尚不清楚。我们的目标是检查影响生长的细胞过程，以评估正常和患病人群的形态学变化。这项基础研究将有助于制定更好的子宫内诊断指标，并最终治疗面部结构性出生缺陷。

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.