BMP-Mediated Tissue Interactions that Pattern the Face

描述(由申请者提供)：我的长期目标是定义控制颅面发育的组织相互作用的细胞和分子基础。了解大脑和面部是如何正常发育的，将有助于更好地理解这些组织中的畸形是如何产生的。从这些见解中，我们将能够产生治疗方法来治疗颅面畸形序列。我的多学科训练侧重于使用生化、分子、细胞、组织学和形态学方法发展颅面肌肉骨骼系统。本申请中提出的工作源于这次培训，并为以后的R01申请奠定了基础。面中部的骨骼来源于位于额鼻和上颌突的神经脊细胞，需要与邻近组织的信号相互作用才能形成适当的图案。我假设在额鼻突中大脑和细胞之间发生的分子相互作用在神经脊和面部外胚层内建立了区域性特征，并且其中一些相互作用是由骨形态发生蛋白(BMP)介导的。为了测试这一点，我将使用逆转录病毒基因传递来激活或抑制鸡胚胎大脑、神经脊和面部外胚层中的特定信号通路。具体地说，我将改变前脑的背腹特征，并评估分子、细胞和形态上的后果。我预计这种治疗会改变BMPS的表达模式，这将导致面部畸形。接下来的两个目标将阐明BMP信号在面部发育中所起的作用。我将通过抑制这些细胞在细胞内传播BMP信号的能力来剖析BMP信号在神经脊、间充质和面部外胚层中的作用。总而言之，这些结果将使我能够确定面部神经脊和外胚层中的区域化基因表达模式是如何由前脑控制的，也将有助于阐明BMP信号如何控制额鼻突起的生长。

DESCRIPTION (provided by applicant): My long-term objective is to define the cellular and molecular basis of tissue interactions that control aspects of craniofacial development. Understanding how development of the brain and face normally occurs will afford a better understand of how malformations arise within these tissues. From these insights, we will be able to generate therapeutic approaches to treat craniofacial malformation sequences. My multidisciplinary training has focused on development of the craniofacial musculoskeletal system using biochemical, molecular, cellular, histological, and morphological approaches. The work proposed in this application stems from this training, and forms the basis for an R01 application at a later date. The skeleton of the midface is derived from neural crest cells located in the frontonasal and maxillary processes, and requires signaling interactions with neighboring tissues for proper patterning. I hypothesize that molecular interactions occurring between the brain and cells in the frontonasal process establish regional characteristics within the neural crest and facial ectoderm and that some of these interactions are mediated by Bone morphogenetic proteins (Bmps). To test this, I will use retroviral gene delivery to activate or suppress specific signaling pathways within the brain, neural crest, and facial ectoderm of chick embryos. Specifically, I will alter the dorsoventral character of the forebrain and assess molecular, cellular, and morphological consequences. I anticipate that expression patterns of Bmps will be altered by this treatment, which will lead to facial dysmorphologies. The next two aims will elucidate the role that Bmp signaling plays during facial development. I will dissect the role of Bmp signaling within the neural crest mesenchyme and facial ectoderm by inhibiting the ability of these cells to propagate Bmp signals within the cell. Collectively, the results will allow me to determine how regionalized gene expression patterns in neural crest and ectoderm of the face are controlled by the forebrain, and will also shed light on how Bmp signals control outgrowth of the frontonasal process.