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: 7581071
• 负责人: JOAN Therese RICHTSMEIER
• 金额: $ 54.72万
• 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/7581071
• 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; 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; 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（由申请方提供）：颅缝早闭（一条或多条颅缝过早融合）是一种常见畸形，每2500例活产婴儿中发生1例，表现出明显的表型变异。颅缝早闭症的颅骨形态不能简单地用骨缝过早融合来解释，而是涉及广泛的头部发育异常。现在已经确定了一些突变与某些临床定义的颅缝早闭症条件。八种颅缝早闭疾病包括Crouzon、Apert和Pfeiffer综合征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中发挥重要和广泛的作用，并且已知通过激活多个途径和信号传导途径之间的相互作用在控制细胞迁移、增殖、分化和存活中发挥关键作用。重要的是，FGFR参与颅骨、脑膜和大脑的发育。我们提出了一个统一的分子和形态学研究的研究，旨在确定中间发育步骤的基因型-表型连续颅缝早闭。我们的方法是一种“表型遗传学”方法，试图将生物表型与其潜在的遗传过程联系起来，例如通过激活信号传导进行区域分化。通过对孤立性颅缝早闭患者的存档MR和CT图像的研究，我们定义了孤立性颅缝早闭和综合征性颅缝早闭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强烈的发育关联。将使用冠状面颅缝早闭和Apert、Crouzon和Pfeiffer综合征病例的CT和MR图像以及这些综合征的两种Fgfr 2小鼠模型的micro-CT和micro-MR的额外3D数据进一步测试这些关联。使用我们的人类头骨和大脑的协变作为时间和空间的指导调查确定的解剖部位，我们将文件模式的异常增殖，分化，凋亡，和Fgf/Fgfr信号在发展中的Fgfr 2 +/S252 W和FgfrcC 342 Y/+突变小鼠的颅骨组织在三个发展阶段。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。我们的形态学分析将为我们的分子研究提供信息，即两种特定的突变如何影响表型发生过程，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的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和Crouzon综合征小鼠模型的数据，以了解这些疾病中整个头部的产生，而不仅仅是闭合缝。