MECHANISMS OF GROWTH AND THE OVERGROWTH SYNDROMES

先天性畸形是美国婴儿发病和死亡的主要原因。尽管这个问题具有压倒性的意义，但大多数先天性畸形的病因仍然难以捉摸。这项研究的长期目标是了解人类畸形的发育和遗传基础。本研究旨在阐明骨生长发育的机制。具体来说，一个由基础和临床科学家组成的多学科协同项目将通过对几种独特动物模型和患者的批判性分析，专注于骨骼形态发生的共同中心主题。在项目一中，Stephen Johnson（遗传学）将利用斑马鱼来确定参与鳍生长和形态发生的局部和系统控制的基因。在Project II中，David Ornitz（药理学）将确定成纤维细胞生长因子受体（FGFRs）在软骨内骨生长发育中的具体作用，并确定FGFR2突变导致Apert综合征的生化机制。在Project II中，Scott Saunders （Pediatrics）将利用一种新的小鼠SGB综合征模型来确定硫酸肝素蛋白聚糖在骨骼生长和分化中的作用，并对受影响的SGB患者进行基因型/表型分析，重点关注骨骼生长发育和发育的异常。在项目四中，Jonathan Gitlin（儿科学）将研究子宫内铜的遗传剥夺对决定骨骼生长和发育的基因修饰的破坏的机制。在Bernard Brownstein（遗传学）的指导下，所有研究人员将利用生物信息学/微阵列研究核心来定义和表征正在研究的动物模型中骨骼生长和形态发生所必需的新遗传程序。行政核心将协调科学活动和资源。综上所述，基础和临床科学家互动合作的结果将为骨骼生长机制提供新的见解，并可能为预防、改善和治疗人类畸形的新策略提供转化发展。

Congenital malformations are the leading cause of infant morbidity and mortality in the United States. Despite the overwhelming significance of this problem, the etiology of most congenital malformations remains elusive. The long-term objective of this research is to understand the developmental and genetic basis of human malformations. The studies in this current proposal are intended to elucidate the mechanisms of bone growth and development. Specifically, a multi-disciplinary, synergistic program of basic and clinical scientists will focus on the common central theme of skeletal morphogenesis through the critical analysis of several unique animal models and patients. In Project I, Stephen Johnson (Genetics) will utilize zebrafish to define the genes involved in local and systematic control of fin growth and morphogenesis. In Project II, David Ornitz (Pharmacology) will determine the specific role of the fibroblast growth factor receptors (FGFRs) in endochondral bone growth and development and define the biochemical mechanisms of a mutation in FGFR2 resulting in Apert syndrome. In Project II, Scott Saunders (Pediatrics) will utilize a novel murine model of Simpson-Golabi-Behmel (SGB) syndrome to define the role of heparan sulfate proteoglycans in bone growth and differentiation and undertake genotype/phenotype analysis of affected SGB patients focusing on the abnormalities in skeletal growth and development and development. In Project IV. Jonathan Gitlin (Pediatrics) will examine the mechanisms of in utero genetic deprivation of cooper on the disruption of modification on genes determining skeletal growth and development. A bioinformatics/microarray research core under the direction of Bernard Brownstein (Genetics) will be utilized by all investigators to define and characterize novel genetic programs essential for skeletal growth and morphogenesis in the animal models being studied. An administrative core will coordinate scientific activities and resources. Taken together, the results of this interactive collaboration of basic and clinical scientists will permit new insights into the mechanisms of skeletal growth and may allow for the translational development of novel strategies to prevent, ameliorate and treat human malformations.