Origins of Sexual Dimorphism in the Craniofacial Skeleton

摘要 男性和女性之间的表型差异，称为性别二型性，是一个关键的生物学变量。 基于性别的变异会产生不同的咬合运动学，肌肉骨骼的患病率和严重程度不同 病情，以及经常需要手术的各种医疗问题。尽管这些数据表明了明显的影响 关于性别对头面部功能和健康的影响，我们知识中的一个关键差距包括 雄性和雌性在表型上开始不同，包括在常见的模式生物如小鼠中， 鸡和鱼。此外，我们不知道产生性别差异的潜在机制 二型性，如遗传背景和激素信号的影响，特别是在面部早期 发展。我们用慈鱼科鱼类模拟人类的性别二态，这些鱼类进化出了异常的 颅面变异，使动物能够通过浸泡在 化学物质，以及反映人类性别二态对下颌骨的影响和遗传变异 背景资料。鉴于控制面部发育的分子在脊椎动物中高度保守， 这项工作可能会识别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、小鼠和鱼类的口腔裂隙。这个项目的核心问题是 性别如何在头面部骨骼的形状上产生功能变化。此阶段2应用程序将专注于 形态、发育时间和候选基因为R01的未来应用奠定基础 重点研究了细胞和分子机制。在目标1中，我们将评估性的发育起源 骨形态和材料性能在性别之间的二形性。我们还将评估遗传风险因素 这进一步增加了基于性别的表型的变异。这些数据将定义性行为何时产生变异 并为未来的R01拨款确定特定的骨骼、时间点和候选基因。在AIM 2，我们将评估性激素在胚胎骨骼发育中的形态作用。我们预测，这些 荷尔蒙不仅调节两性的骨骼模式，而且荷尔蒙信号的变化也驱动着男性和女性 性别二型性的差异和物种特有的表现。这一目标的实现将延长我们的 激素在成人骨生物学到胚胎阶段的知识，这是目前我们的一大空白 理解。我们还将为未来的机制研究确定发育窗口和关键细胞类型 在R01应用程序中。该项目的概念是最初的SC-TRIMH，因为潜在的整合在 并利用临床前评估核心(PAC)、多尺度计算模型(MCM)核心、 高级制造与测试(AFT)核心和管理核心。它还与另外两个 Cobres在克莱姆森大学支持克莱姆森大学基因组和生物信息学设施， 对于AIM 1.2来说很重要。

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.