Origins of Sexual Dimorphism in the Craniofacial Skeleton

总结 雄性和雌性之间的表型差异，称为性二态性，是一个重要的生物学变量。 基于性别的变化产生不同的咬运动学，不同的患病率和严重程度的肌肉骨骼 条件和各种医疗问题，往往需要手术。尽管这些数据表明， 性别对颅面功能和健康的影响，我们知识中的一个关键空白包括发育阶段， 其中雄性和雌性开始在表型上不同，包括在常见的模式生物如小鼠中， 鸡和鱼。此外，我们不知道产生性差异的潜在机制， 二型性，如遗传背景和激素信号的影响，特别是在早期面部 发展我们用慈鲷鱼来模拟人类的两性异形， 颅面变化，通过将动物浸入 化学物质，并反映人类性别二型性方面的影响，对下颌骨和变异，由于遗传 背景鉴于控制面部发育的分子在脊椎动物中高度保守， 这项工作可能会发现调节人类肌肉骨骼变异的新机制和基因。为 例如，Pdgfra调节人类、小鼠和鱼类的口面裂。这个项目的核心问题是 性别如何导致颅面骨骼形状的功能变化。第二阶段的申请将集中在 在形态学、发育时间和候选基因方面的研究，为R 01的未来应用奠定基础 专注于细胞和分子机制。在目标1中，我们将评估性行为的发育起源， 两性之间骨骼形状和材料特性的二型性。我们还将评估遗传风险因素 从而进一步增加了基于性别的表型的变异。这些数据将确定性别何时会产生 颅面骨骼，并确定特定的骨骼，时间点和候选基因，为未来的R 01赠款。在Aim中 2、我们将评估性激素在胚胎骨发育中的形态学作用。我们预测， 激素不仅调节两性的骨骼模式， 差异和性别二型的物种特异性表现。这一目标的实现将使我们的 激素在成人骨生物学到胚胎阶段的知识，这是目前我们的一个主要空白， 认识我们还将确定发育窗口和关键细胞类型，为未来的机制研究 在R 01应用程序中。该项目是概念化的初始SC-TRIMH，由于潜在的整合， 这一组，并利用临床前评估核心（PAC），多尺度计算建模（MCM）核心， 先进制造和测试（AFT）核心和管理核心。它还与其他两个 克莱姆森大学的COBRES支持克莱姆森大学基因组学和生物信息学设施， 对目标1.2很重要。

SUMMARY Phenotypic differences between males and females, termed sexual dimorphism, are a critical biological variable. Sex-based variation produces distinct biting kinematics, differential prevalence and severity of musculoskeletal conditions, and a variety of medical issues often requiring surgery. Despite these data indicating a clear impact of sex on craniofacial function and health, a critical gap in our knowledge includes the developmental stage at which males and females begin to differ in phenotype, including in common model organisms such as mice, chickens, and fishes. Further, we do not know the underlying mechanisms that generate variation in sexual dimorphism, such as the effects of genetic background and hormone signaling, particularly in early facial development. We model human sexual dimorphism using cichlid fishes, which have evolved exceptional craniofacial variation, enable easy manipulation of embryonic development through immersion of animals in chemicals, and mirror human sexual dimorphism in terms of effects on the mandible and variation due to genetic background. Given that the molecules that control facial development are highly conserved across vertebrates, this work may identify new mechanisms and genes that regulate musculoskeletal variation in humans. For example, Pdgfra regulates orofacial clefting in humans, mice, and fishes. The central question of this project is how sex generates functional variation in shape of the craniofacial skeleton. This Phase 2 application will focus on morphology, developmental time, and candidate genes to lay the foundations for future R01 applications focused on cellular and molecular mechanisms. In Aim 1, we will assess developmental origins of sexual dimorphism in bone shape and material properties between the sexes. We will also evaluate genetic risk factors that add further variation to sex-based phenotypes. These data will define when sex generates variation in the craniofacial skeleton and identify specific bones, timepoints, and candidate genes for a future R01 grant. In Aim 2, we will assess the morphological role of sex hormones in embryonic bone development. We predict that these hormones not only regulate bone patterning in both sexes, but variation in hormone signaling drives male-female differences and species-specific presentation of sexual dimorphism. Completion of this aim will extend our knowledge of hormones in adult bone biology to embryonic stages, which is currently a major gap in our understanding. We will also identify developmental windows and critical cell types for future mechanistic study in an R01 application. This project was conceptualized for an initial SC-TRIMH due to potential integration within this group and utilizes the Pre-clinical Assessment Core (PAC), Multiscale Computational Modeling (MCM) core, Advanced Fabrication & Testing (AFT) core, and the Administrative Core. It also synergizes with two other COBRES at Clemson University that support the Clemson University Genomics and Bioinformatics Facility which is important for Aim 1.2.