Unraveling the mechanisms of prenatal-onset disorders affecting the skeleton

揭示影响骨骼的产前发病机制

• 批准号: 9061402
• 负责人: Deborah Krakow
• 金额: $ 33.37万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9061402
• 关键词: Affect; Arthritis; Biological; Biology; Bone Diseases; Bone Growth; Cartilage; Clinical; Clinical Treatment; Complement; Consanguinity; DNA; Data; Decision Making; Defect; Development; Developmental Course; Diagnosis; Disease; Epiphysial cartilage; Family; Gene Expression; General Population; Genes; Genetic; Genetic Counseling; Goals; Growth; Health; Hereditary Disease; Histologic; Homeostasis; Individual; Inheritance Patterns; International; Knowledge; Lead; Maps; Medical; Molecular; Natural History; Onset of illness; Osteoporosis; Outcome; Pathway interactions; Periosteum; Phenotype; Physically Handicapped; Registries; Resources; Role; Skeletal Development; Skeleton; Structure; Survivors; Ultrasonography; Work; base; bone; clinical care; exome sequencing; expectation; gene discovery; improved; insight; novel; prenatal; reproductive; research study; skeletal abnormality; skeletal disorder; skeletal dysplasia; spine bone structure

DESCRIPTION (provided by applicant): The skeletal dysplasias (SDs) are a heterogeneous group of genetic disorders associated with abnormalities in the skeleton that lead to long-term physical disabilities in survivors and lethal skeletal abnormalities in some cases. Over the last 30 years, we have collected material on more than 18,000 skeletal dysplasia cases, more than half presenting to various degrees in the prenatal period. This project is aimed at defining the ultrasound, clinical, histologic, molecular, and pathophysiologic features of novel or poorly delineated prenatal onset skeletal disorders. The goals of this project are to define and solve the molecular basis of these disorders, thereby increasing our knowledge of skeletal development and biology and improving our understanding of the mechanisms and developmental course of prenatal onset skeletal dysplasias. We will achieve these goals through the following Specific Aims: 1. Define and characterize novel skeletal dysplasias. Using the large number of previously ascertained cases, we have determined that approximately 10% of prenatal onset skeletal dysplasias cannot be assigned a specific diagnosis. We will take advantage of this unique resource of unclassified cases by defining novel prenatal onset skeletal disorders. We will first concentrate on phenotyping and classifying poorly defined, yet frequently encountered, disorders with the findings of bent bones and multiple vertebral segmentation defects. 2. Identify the underlying genetic basis of novel skeletal dysplasias. This Aim will capitalize on the availability of DNA for the disorders defined in Aim 1 and will use exome sequencing as the primary approach to identifying their genetic basis. The exome sequencing data will be filtered based on the pattern of inheritance, loci identified by homozygosity mapping in selected cases of recessive disorders with parental consanguinity, and gene expression in the target tissues, growth plate cartilage and perichondrium/periosteum. For the perichondrium/periosteum, our preliminary data on bent bone disorders have identified an important yet unappreciated role for the effects of genes expressed in perichondrium/periosteum on skeletal development. It is thus our expectation that many of the bent bone disorders that we will characterize, define and solve will result from genes with high expression in this region of the developing skeleton. Identifying the molecular defect in these understudied disorders, will be complemented by experiments aimed at determining their pathogenetic mechanisms, and will provide molecular, histologic and clinical structures within which to understand and classify this diverse group of disorders. The expected outcomes of the proposed work will improve our understanding of currently poorly delineated prenatal onset skeletal disorders. Of medical importance to the general population, discovering the genes and pathways in these prenatal onset genetic skeletal dysplasias will identify previously unknown mechanisms and pathways involved in normal growth, bone and cartilage homeostasis and the development of arthritis and osteoporosis, thus providing essential data for developing rational clinical care and treatment paradigms.

描述（由申请人提供）：骨骼发育不良（SDs）是一组异质性遗传疾病，与骨骼异常相关，导致幸存者长期身体残疾，在某些情况下导致致命的骨骼异常。在过去的30年里，我们收集了18,000多例骨骼发育不良病例的资料，其中一半以上在产前有不同程度的表现。本项目旨在定义新的或未明确描述的产前发病骨骼疾病的超声、临床、组织学、分子和病理生理特征。这个项目的目标是定义和解决