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Origins of Sexual Dimorphism in the Craniofacial Skeleton

颅面骨骼性别二态性的起源

基本信息

批准号：
10714167
负责人：
Kara E Powder
金额：
$ 23.04万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714167
关键词：
Address Adult Affect Animals Bioinformatics Biological Biology Bite Bone Density Bone Development Candidate Disease Gene Cells Centers of Research Excellence Chemicals Chickens Cichlids Cleft lip with or without cleft palate Data Degenerative polyarthritis Development Disease Embryo Embryonic Development Environment Estradiol Face Female Fishes Foundations Future Genes Genetic Genetic Polymorphism Genomics Gonadal Steroid Hormones Grant Health Hormones Human Immersion Jaw Knowledge Libido Mandible Mechanics Medical Mentorship Modeling Molecular Morphology Movement Mus Musculoskeletal Musculoskeletal System Operative Surgical Procedures Outcome Paper Patients Pattern Phase Phenotype Physiologic Ossification Prevalence Progesterone Property Publishing Regulator Genes Research Project Grants Risk Factors Role Series Severities Shapes Signal Transduction Skeleton System Temporomandibular Joint Dysfunction Syndrome Testing Time Universities Variant Vertebrates Woman Work X-Ray Computed Tomography bone candidate identification cell type craniofacial craniofacial development cranium fabrication genetic analysis genetic risk factor hormonal signals human model improved innovation insight kinematics male men microCT model organism multi-scale modeling novel therapeutics optical imaging orofacial cleft pre-clinical assessment sex sexual dimorphism shape analysis symposium synergism transcriptome sequencing

项目摘要

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.

总结