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: 8675030
• 负责人: Deborah Krakow
• 金额: $ 34.61万
• 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/8675030
• 关键词: Affect; Arthritis; Biological; Biology; Bone Diseases; Bone Growth; Cartilage; Clinical; Clinical Treatment; Complement; Consanguinity; DNA; Data; Decision Making; Defect; Development; Diagnosis; Disease; Epiphysial cartilage; Family; Gene Expression; General Population; Genes; Genetic; Genetic Counseling; Goals; Growth; Hereditary Disease; Histologic; Homeostasis; Individual; Inheritance Patterns; International; Knowledge; Lead; Maps; Medical; Molecular; Natural History; Onset of illness; Osteoporosis; Outcome; Pathway interactions; Periosteum; Phenotype; Registries; Resources; Role; Skeletal Development; Skeleton; Structure; Survivors; Ultrasonography; Work; base; bone; clinical care; disability; exome sequencing; expectation; gene discovery; improved; insight; novel; prenatal; public health relevance; 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）是与骨骼异常相关的一组遗传疾病，在某些情况下会导致幸存者的长期身体残疾，并导致幸存者的长期身体残疾。在过去的30年中，我们收集了18,000多例骨骼发育异常病例的材料，在产前期间有超过一半的材料。该项目旨在定义新型或划定不良的产前骨骼疾病的超声，临床，组织学，分子和病理生理特征。该项目的目标是定义和解决 这些疾病的分子基础，从而增加了我们对骨骼发育和生物学的了解，并提高了我们对产前发作骨骼发育不良的机制和发育过程的理解。我们将通过以下特定目的实现这些目标：1。定义并表征新颖的骨骼发育不良。使用大量先前确定的病例，我们确定大约10％的产前发作骨骼发育不良，无法分配特定的诊断。我们将通过定义新的产前发作骨骼疾病来利用这种未分类的病例的独特资源。我们将首先专注于表型，并分类弯曲骨骼和多个椎骨分割缺陷的发现，但经常遇到的疾病却经常遇到。 2。确定新型骨骼发育不良的潜在遗传基础。该目标将利用DNA的可用性用于AIM 1中定义的疾病，并将使用外显子测序作为识别其遗传基础的主要方法。外显子组测序数据将根据遗传模式进行过滤，该基因座通过纯合性映射在某些具有父母血缘性的隐性疾病的病例中，以及在靶组织中的基因表达，生长板软骨和perichondrium/骨膜中的基因表达。对于perichondrium/骨膜，我们关于弯曲骨疾病的初步数据已经确定了在perichondrium/骨膜中表达的基因对骨骼发育的重要作用。因此，我们的期望是，我们将表征，定义和求解的许多弯曲骨疾病将是由于在发展骨骼的该区域中表达高表达的基因所致。识别这些研究疾病中的分子缺陷，将通过旨在确定其致病机制的实验来补充，并将提供分子，组织学和临床结构，以了解和分类这一多样的疾病群。拟议工作的预期结果将提高我们对当前划定的产前发作骨骼疾病的理解。对普通人群的医学重要性，发现这些产前开始的基因和途径遗传骨骼骨骼发育异常将确定以前未知的机制和途径，涉及正常生长，骨骼和软骨稳态以及关节炎和骨质疏松症的发展，从而为开发临床护理和治疗范式提供了必要的数据。