Phenogenetics of Skull and Brain Integration in Craniosynostosis

颅缝早闭中颅骨和大脑整合的表观遗传学

• 批准号: 7829468
• 负责人: Ethylin Wang Jabs
• 金额: $ 38.32万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7829468
• 关键词: Affect; Amino Acids; Anatomy; Apert syndrome; Apert-Crouzon syndrome; Apoptosis; Archives; Be++ element; Beryllium; Biomechanics; Brain; Breeding; Calvaria; Cell physiology; Cephalic; Characteristics; Child; Clinical; Craniosynostosis; Data; Development; Developmental Process; Disease; Embryo; Embryonic Development; Event; FGFR2 gene; Funding; Gene Structure; Genetic; Genotype; Goals; Head; Human; Image; Inbred Mouse; Individual; Infant; Investigation; Joint structure of suture of skull; Knowledge; Lead; Literature; Live Birth; Magnetic Resonance Imaging; Maps; Methods; Modeling; Molecular; Morphology; Mus; Mutant Strains Mice; Mutation; Nature; Parents; Pathogenesis; Pathway interactions; Patients; Pattern; Pfeiffer Syndrome; Phenotype; Population; Process; Production; Recovery; Research; Resources; Sampling; Series; Shapes; Signal Transduction; Site; Staging; Surgical sutures; System; Testing; Three-dimensional analysis; Tissues; United States National Institutes of Health; Variant; Work; X-Ray Computed Tomography; base; bone; brain shape; coronal suture; craniofacial; cranium; design; embryo tissue; human data; malformation; molecular imaging; mouse model; mutant; premature; public health relevance; relating to nervous system; response; spatiotemporal

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.

描述（由申请人提供）：颅缝早闭，即一根或多根颅缝的过早融合，是一种常见的畸形，每 2500 名活产儿中就有 1 人发生颅缝早闭，并显示出颅骨表型的显着变异。母体 R01 (R01-DE018500) 提出了一项分子和形态学数据的统一研究，旨在确定颅缝早闭基因型-表型连续体中的中间发育步骤。我们正在使用分别来自阿佩尔综合征和克鲁宗综合征的 Fgfr2+/S252W 和 Fgfr2cC342Y/+ 小鼠模型的显微 CT 和显微 MR 图像的 3D 数据来测试头骨和大脑之间的发育关联。利用我们对人类颅骨和大脑的研究确定的解剖部位，以及我们在对这些小鼠模型的分析中确定的大脑和颅骨共变模式作为时间和空间指导，我们将记录突变小鼠在三个发育阶段的颅骨组织发育中的异常增殖、分化、凋亡和 Fgf/Fgfr 信号传导的模式。我们的假设是，形成性颅骨和大脑中异常 Fgf/Fgfr 信号传导的时空图是一系列发育事件的基础，这些发育事件导致这些部位局部的异常细胞过程，并最终导致颅缝早闭中的异常头部和大脑形状。 我们对携带 Fgfr2+/P253R 突变的近交小鼠取得了重要的初步结果，这种直系同源突变发生在三分之一的阿佩尔综合征患者中。我们的初步数据表明，尽管 S252W 和 P253R 突变发生在相邻氨基酸中，但每种突变都与统计上不同的大脑和颅骨表型相关。我们量化了携带 Fgfr2+/P253R 突变的 P0 小鼠冠状缝闭合变化的增加，并记录了这种变化与两个模型中大脑和颅骨 3D 形态之间的共变模式之间的关系。我们的目标是揭示有助于缝合线通畅的脑-颅骨关系的发育规则。通过将携带 Fgfr2+/P253R 突变的小鼠添加到我们的研究设计中，可以最有效地实现这一目标。 为了响应通知编号 (NOT-OD-09-058) 和通知标题：NIH 宣布恢复法案资金用于竞争性修订申请的可用性，我们将 Fgfr+/P253R Apert 小鼠添加到我们的调查中，该小鼠是在提交母 R01 申请后才开发的。我们建议使用百分位数为 0.2 的母 R01 申请中提出的相同分析方法来研究 Fgfr+/P253R Apert 小鼠的表遗传学，并比较在相同遗传背景下培育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，了解两种阿佩尔综合征突变和三种不同的 Fgfr2 突变如何比较其表观过程，从而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，其定义是颅骨（最常见的是颅骨）的过早融合。我们的目标是利用患有非综合征性冠状颅缝早闭和阿佩尔综合征、克鲁松综合征和普法伊弗综合征的人群的数据，以及阿佩尔综合征小鼠模型的数据，研究颅缝早闭中颅骨和大脑发育的综合性质，以了解这些疾病中整个头部的发育，而不仅仅是闭合缝的发育。