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: 8015991
• 负责人: JOAN Therese RICHTSMEIER
• 金额: $ 52.25万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-10 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015991
• 关键词: Affect; Age; Anatomy; Apert syndrome; Apert-Crouzon syndrome; Apoptosis; Archives; Binding; Biological; Biomechanics; Brain; Calvaria; Cell physiology; Cephalic; Characteristics; Clinical; Craniosynostosis; Data; Development; Developmental Process; Disease; Elements; Embryo; Embryonic Development; Event; Fibroblast Growth Factor Receptor 1; Fibroblast Growth Factor Receptors; Gene Structure; Genetic; Genetic Processes; Genotype; Head; Health; Human; Image; Infant; Investigation; Joint structure of suture of skull; Knowledge; Lead; Ligands; Literature; Live Birth; Magnetic Resonance Imaging; Maps; Meninges; Molecular; Morphology; Mus; Mutant Strains Mice; Mutation; Nature; Pathway interactions; Pattern; Perinatal; Pfeiffer Syndrome; Phenotype; Play; Population; Positioning Attribute; Process; Production; Protein Tyrosine Kinase; Research; Research Design; Resources; Role; Sampling; Series; Shapes; Signal Pathway; Signal Transduction; Site; Staging; Surgical sutures; Syndrome; System; Testing; Three-dimensional analysis; Time; Tissues; Variant; Work; base; bone; brain shape; cell motility; craniofacial; cranium; data modeling; developmental genetics; embryo tissue; gene function; human data; malformation; mouse model; mutant; postnatal; premature; relating to nervous system; spatiotemporal; suture fusion; trait

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 phenotypes. The skull shape in craniosynostosis can not be explained simply by the premature fusion of sutures, but involves widespread abnormal development of the head. A number of mutations have now been identified that are associated with certain clinically defined craniosynostosis conditions. Eight of the craniosynostosis disorders including Crouzon, Apert and Pfeiffer syndromes are caused by mutations in fibroblast growth factor receptors (FGFR)-1, -2 or -3. FGFR tyrosine kinases and their ligands play fundamental and widespread roles in development and are known to play a crucial role in the control of cell migration, proliferation, differentiation and survival by activation of multiple pathways and interaction among signaling pathways. Importantly, FGFRs are involved in development of the skull, meninges, and the brain. We propose a unifying study of molecular and morphological research aimed at identifying the intermediate developmental steps in the genotype-phenotype continuum of craniosynostosis. Ours is a "phenogenetic" approach that attempts to connect biological phenotypes with their underlying genetic processes such as regional differentiation by activation of signaling. Through a study of archived MR and CT images of humans with isolated craniosynostosis we defined phenotypic correlations of traits on skull and brain in isolated and syndromic craniosynostosis. These correlations are indicative of strong developmental associations between brain and skull. These associations will be further tested using additional 3D data from CT and MR images of cases of coronal craniosynostosis and Apert, Crouzon and Pfeiffer syndromes and micro-CT and micro-MR of two Fgfr2 mouse models for these syndromes. Using anatomical sites identified by our investigations of human skull and brain covariation as a temporal and spatial guide, we will document patterns of abnormal proliferation, differentiation, apoptosis, and Fgf/Fgfr signaling in developing cranial tissues of Fgfr2+/S252W and FgfrcC342Y/+ 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. Our morphological analyses will inform our molecular investigations of how two particular mutations affect 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 and Crouzon syndrome to understand the production of the entire head in these disorders and not just the closed suture.

描述（由申请人提供）：颅缝闭合，一个或多个颅缝的过早融合，是一种常见的畸形，每2500个活产婴儿中就有1个发生，并表现出显着的表型变异。颅缝闭合症的颅骨形状不能简单地用缝合线过早融合来解释，而是涉及头部广泛的异常发育。现在已经确定了一些突变与某些临床定义的颅缝闭锁有关。包括Crouzon、Apert和Pfeiffer综合征在内的8种颅缝闭锁疾病是由成纤维细胞生长因子受体(FGFR)-1、-2或-3突变引起的。FGFR酪氨酸激酶及其配体在发育过程中发挥着基础和广泛的作用，并且通过激活多种途径和信号通路之间的相互作用，在细胞迁移、增殖、分化和存活的控制中起着至关重要的作用。重要的是，fgfr参与颅骨、脑膜和大脑的发育。我们提出统一的分子和形态学研究，旨在确定颅缝闭锁基因型-表型连续体的中间发育步骤。我们的研究是一种“表型”方法，试图将生物表型与其潜在的遗传过程（如通过激活信号的区域分化）联系起来。通过对孤立性颅缝闭锁患者存档的MR和CT图像的研究，我们定义了孤立性和综合征性颅缝闭锁患者颅骨和大脑特征的表型相关性。这些相关性表明大脑和头骨之间存在着很强的发育联系。这些关联将通过冠状颅缝闭闭病例的CT和MR图像的额外3D数据以及用于这些综合征的两种Fgfr2小鼠模型的micro-CT和micro-MR进一步测试。利用我们在人类颅骨和大脑共变研究中确定的解剖位点作为时空指导，我们将记录Fgfr2+/S252W和FgfrcC342Y/+突变小鼠在三个发育阶段的异常增殖、分化、凋亡和Fgf/Fgfr信号传导模式。我们的假设是，形成颅骨和大脑中异常Fgf/Fgfr信号的时空图是一系列发育事件的基础，这些事件导致这些部位的异常细胞过程，并最终导致颅缝闭闭患者的头部和大脑形状异常。我们的形态学分析将为我们的分子研究提供信息，以了解两种特定突变如何影响表型过程，从而产生导致颅缝闭合表型的发育关系。公共卫生相关性：颅缝闭锁是一种常见的畸形，其特征是颅骨过早融合，最常见的是颅骨。我们的目的是利用来自非综合征性冠状颅缝闭闭和Apert、Crouzon和Pfeiffer综合征人群的数据，以及Apert和Crouzon综合征小鼠模型的数据，研究颅缝闭闭患者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产生，而不仅仅是闭合缝合线。