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

连续表型变异在面部结构缺陷中的作用

基本信息

批准号：
8628660
负责人：
Benedikt Hallgrimsson
金额：
$ 33.05万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-23 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628660
关键词：
3-Dimensional Address Affect Apoptosis Applications Grants Attention Basic Science Biochemical Birds Bone Morphogenetic Proteins Brain Cell Death Cell Proliferation Cell Survival Cell physiology Cells Cessation of life Congenital Abnormality Data Defect Development Diagnostic Disease Early Diagnosis Ectoderm Embryo Emigrations Erinaceidae Exhibits FGFR2 gene Face Fibroblast Growth Factor Figs - dietary Gene Expression Profile Genetic Growth Head Human Image Intervention Jaw Lead Ligands Mammals Mesenchyme Methods Metric Microforms Molecular Molecular and Cellular Biology Morphology Mutation Neural Crest Neural Crest Cell Outcome Pathway interactions Patients Pattern Phenotype Population Primordium Production Prosencephalon Regulation Research Research Personnel Resolution Role SHH gene Series Shapes Signal Pathway Signal Transduction Signaling Molecule Stream Structural Congenital Anomalies Testing Time Translating Variant Work base craniofacial gain of function imaging modality in utero loss of function malformation mind control mutant public health relevance receptor research study response tool transcription factor

项目摘要

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.

描述（由申请人提供）：表型变异是颅面出生缺陷的标志，但理解变异形态学与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，因此很难确定可变形态学的基础。然而，调节面部形态的分子途径可能集中在一组较小的细胞过程上。在这项工作中，我们将重点放在控制面部原基生长的两个细胞过程上，因为生长的差异会导致表型的变化。我们假设，通过离散地改变调节上颌大轴模式的分子信号通路，最终控制细胞增殖和凋亡的基因表达模式的改变将产生连续的表型变异。在每个Aim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。在第三个特定目标中，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Aim 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Aim 2中，我们将破坏神经嵴间质内调节细胞增殖的信号。在Aim 3中，我们将干扰来自大脑和神经嵴内调节凋亡和细胞增殖的信号。在每个Aim中，我们将使用3-D和2-D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途径的激活、信号分子的表达、受体和控制细胞增殖和存活、细胞增殖和细胞死亡的转录因子联系起来。在每个目标中，我们提出生化或基于细胞的实验来改善我们的治疗引起的表型变化，并直接测试改变形态产生的机制。这些实验将使用形态计量学分析进行评估，因为这种方法使我们能够客观、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地评估生长在面部发育过程中产生形态变异的作用。这种方法将使研究人员能够将特定的基因破坏与调节面部形态的分子变化和细胞过程联系起来。此外，随着高分辨率子宫内成像方法的出现，我们的研究将为开发早期检测面部畸形的参数奠定基础，并可能为子宫内治疗开辟道路。