Phenogenetics of Skull and Brain Integration in Craniosynostosis

描述（由申请人提供）：颅缝早闭，即一条或多条颅缝过早融合，是一种常见畸形，每2500名活产婴儿中就有1例发生，并且表现出颅骨表型的显着变化。亲本R 01（R 01-DE 018500）提出了一项分子和形态学数据的统一研究，旨在确定颅缝早闭的基因型-表型连续体中的中间发育步骤。我们正在使用来自Fgfr 2 +/S252 W和Fgfr 2cC 342 Y/+小鼠模型的显微CT和显微MR图像的3D数据分别测试Apert和Crouzon综合征的颅骨和大脑之间的发育关联。使用我们的人类头骨和大脑的调查，以及在我们的分析这些小鼠模型作为一个时间和空间的指导模式的大脑和头骨协变确定的解剖部位，我们将文件异常增殖，分化，凋亡和Fgf/Fgfr信号模式的突变小鼠在三个发展阶段的发展中的颅组织。我们的假设是，在形成的颅骨和大脑的异常Fgf/Fgfr信号的时空地图是一系列的发展事件，导致异常的细胞过程本地这些网站，并最终导致异常的头部和大脑形状的颅缝早闭的基础。 我们对Fgfr 2 +/P253 R突变的近交系小鼠进行了重要的初步研究，该突变发生在三分之一的Apert综合征患者中。我们的初步数据表明，尽管S252 W和P253 R突变发生在相邻的氨基酸中，但每个突变与统计学上不同的脑和颅骨表型相关。我们量化了携带Fgfr 2 +/P253 R突变的P0小鼠冠状缝闭合的变化，并记录了这种变化与两种模型中大脑和颅骨3D形态之间的协变模式之间的关系。我们的目标是揭示有助于缝合通畅的脑-颅关系的发育规则。这可以通过将携带Fgfr 2 +/P253 R突变的小鼠添加到我们的resaserch设计中来最有效地实现。 针对通知编号（NOT-OD-09-058）和通知标题：NIH宣布恢复法案资金可用于竞争性修订申请，我们在调查中增加了Fgfr+/P253 R Apert小鼠，该小鼠在提交父代R 01申请后才开发。我们建议使用与亲本R 01申请（百分位数为0.2）中提出的相同分析方法研究Fgfr+/P253 R Apert小鼠的表型遗传学，并比较在相同遗传背景下繁殖的这三种小鼠模型的结果。我们的形态学分析将为我们的分子研究提供信息，了解两种Apert综合征突变和三种不同的Fgfr 2突变如何在其表型发生过程中进行比较，以产生导致颅缝早闭表型的发育关系。 公共卫生相关性：颅缝早闭是一种常见的畸形，其定义为颅骨的过早融合，最常见的是颅骨的过早融合。我们的目的是研究颅缝早闭患者颅骨和大脑发育的综合性质，使用来自非综合征冠状颅缝早闭和Apert、Crouzon和Pfeiffer综合征人群的数据，以及来自Apert综合征小鼠模型的数据，以了解这些疾病中整个头部的发育，而不仅仅是闭合缝。

DESCRIPTION (provided by applicant): Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation occurring in 1 out of every 2500 live births, and shows marked variation of cranial phenotypes. The parent R01 (R01-DE018500) proposed a unifying study of molecular and morphological data aimed at identifying intermediate developmental steps in the genotype-phenotype continuum of craniosynostosis. We are testing developmental associations between skull and brain using 3D data from micro-CT and micro-MR images of the Fgfr2+/S252W and Fgfr2cC342Y/+ mouse models for Apert and Crouzon syndromes, respectively. Using anatomical sites identified by our investigations of human skull and brain, as well as patterns of brain and skull covariation identified in our analyses of these mouse models as a temporal and spatial guide, we will document patterns of abnormal proliferation, differentiation, apoptosis, and Fgf/Fgfr signaling in developing cranial tissues of mutant mice at three developmental stages. Our hypothesis is that the spatiotemporal map of abnormal Fgf/Fgfr signaling in formative skull and brain is the basis for a series of developmental events that result in anomalous cellular processes local to those sites and ultimately result in the abnormal head and brain shape in craniosynostosis. We have important preliminary results on inbred mice with a Fgfr2+/P253R mutation, the orthologous mutation occuring in one third of Apert syndrome patients. Our preliminary data suggest that although the S252W and P253R mutations occur in adjacent amino acids, each mutation is associated with statistically different brain and skull phenotypes. We quantify increased variation in coronal suture closure in P0 mice carrying the Fgfr2+/P253R mutation and document a relationship between this variation and the pattern of covariation between brain and skull 3D morphology in both models. Our goal is to uncover the developmental rules of brain-skull relationships that contribute to suture patency. This can be most efficiently accomplished by adding mice carrying the Fgfr2+/P253R mutation to our resaserch design. In response to Notice Number (NOT-OD-09-058) and Notice title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications, we add to our investigations the Fgfr+/P253R Apert mouse, that was not developed until after the parent R01 application was submitted. We propose to study the phenogenetics of the Fgfr+/P253R Apert mouse using the same methods of analysis proposed in the parent R01 application that received a percentile of 0.2, and to compare results among these three mouse models that are bred on the same genetic background. Our morphological analyses will inform our molecular investigations of how the two Apert syndrome mutations, and the three different Fgfr2 mutations, compare in their phenogenetic processes to produce developmental relationships that lead to craniosynostosis phenotypes. PUBLIC HEALTH RELEVANCE: Craniosynostosis is a common malformation which is defined by the premature fusion of skull bones, most commonly those of the calvaria. Our aims are to study the integrated nature of skull and brain development in craniosynostosis using data from human populations with nonsyndromic coronal craniosynostosis and Apert, Crouzon and Pfeiffer syndrome, as well as data from mouse models for Apert syndrome to understand the development of the entire head in these disorders and not just the closed suture.