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）：颅突式症，一个或多个颅骨缝合线的过早融合，是每2500个活生生中有1个发生的常见畸形，并且显示出明显的颅骨表型变化。母体R01（R01-DE018500）提出了一项对分子和形态数据的统一研究，旨在鉴定颅底症基因型 - 表型连续性中的中间发育步骤。我们正在使用FGFR2+/S252W和FGFR2CC342Y/+小鼠模型的APERT和CROUZON综合征的FGFR2+/S252W和FGFR2CC342Y/+小鼠模型的3D数据测试头骨和大脑之间的发育关联。使用我们对人类头骨和大脑的研究确定的解剖位点，以及在我们将这些小鼠模型作为时间和空间指南的分析中鉴定出的大脑和颅骨协方差的模式，我们将记录异常增殖，分化，凋亡，凋亡，凋亡，凋亡，FGF/FGF/FGF/FGFR信号在三个发展中的发育型脑部三个发展中的形成。我们的假设是，形成性头骨和大脑中FGF/FGFR异常信号传导的时空图是一系列发育事件的基础，这些事件导致这些位点的异常细胞过程，并最终导致颅骨表现的异常头部和脑形。 我们对具有FGFR2+/P253R突变的近交小鼠有重要的初步结果，即APERT综合征患者中三分之一发生的直系突变。我们的初步数据表明，尽管S252W和P253R突变发生在相邻的氨基酸中，但每个突变都与统计上不同的大脑和颅骨表型有关。我们量化了携带FGFR2+/P253R突变的P0小鼠中冠状缝合线闭合的变化，并记录了这两种模型中这种变化与大脑和头骨3D形态之间的协方差之间的关系。我们的目标是揭示有助于缝合通畅的脑部关系的发展规则。通过将携带FGFR2+/P253R突变携带的小鼠添加到我们的重塑设计中，这可以最有效地完成。 为了响应通知号（NOT-OD-09-058）和通知标题：NIH宣布为有竞争力的修订申请提供恢复ACT资金，我们将FGFR+/P253R APERT鼠标添加到调查中，直到提交父级R01申请后才开发。我们建议使用在父级R01应用中提出的相同的分析方法研究FGFR+/P253R Apert小鼠的苯遗传学，该分析方法接受了0.2的百分位数，并比较了以相同遗传背景繁殖的三种小鼠模型之间的结果。我们的形态分析将为我们关于两个APERT综合征突变以及三种不同的FGFR2突变如何进行分子研究，以比较其态遗传过程，以产生发育关系，从而导致颅面性表型。 公共卫生相关性：颅骨突变是一种常见的畸形，这是由头骨骨骼过早融合来定义的，骨骼骨骼（通常是瓦尔瓦里亚的骨骼）。我们的目的是利用来自非疾病的冠状颅骨颅骨促颅和APERT，CROUZON和PFEIFFER综合征的数据以及来自Apert综合征的鼠标模型的数据来了解整个疾病的鼠标模型的数据，从而了解整个疾病的整个问题，而不仅仅是关闭的Suture sauter，我们的目的是研究颅突发作中头骨和大脑发育的综合性质。