Short-rib polydactyly and the skeletal ciliopathies

短肋多指症和骨骼纤毛病

• 批准号: 9304790
• 负责人: DANIEL H COHN
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-29 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304790
• 关键词: Animal Model; Biological; Biology; Cell Line; Cells; Cilia; Complex; Cultured Cells; DNA; Data; Defect; Disease; Dissection; Dynein ATPase; Environment; Erinaceidae; Family; Fibroblast Growth Factor; Frequencies; Gene Mutation; Genes; Genetic; Genetic Counseling; Genetic Heterogeneity; Genetic screening method; Genomic approach; Goals; Human; Inborn Genetic Diseases; International; Intestines; Lead; Medical Genetics; Missense Mutation; Modeling; Molecular; Molecular Genetics; Morphology; Motor; Mus; Mutation; Outcome; Pathway interactions; Patients; Perinatal; Phenotype; Phosphotransferases; Polydactyly; Registries; Regulation; Resources; Sampling; Signal Pathway; Signal Transduction; Skeletal Development; Skeleton; Testing; Tissues; Work; chondrodysplasia; ciliopathy; cilium biogenesis; cohort; experimental study; gene discovery; genome sequencing; improved; insight; public health relevance; rib bone structure; skeletal; skeletal disorder; skeletal dysplasia; skeletal tissue; skeletogenesis; translational impact

 DESCRIPTION (provided by applicant): Genome sequencing is revolutionizing our understanding of skeletal biology. By determining the molecular basis of the skeletal dysplasias, a heterogeneous group of inherited disorders that have a profound effect on the skeleton, unanticipated molecules and mechanisms essential for normal skeletal development are being revealed. While the genes associated with most of the common skeletal dysplasias have been determined, short-rib polydactyly (SRP) is the most frequent perinatal lethal skeletal disorder for which the biological basis and mechanism are incompletely understood. SRP is also the most common skeletal ciliopathy, so determining the molecular basis and mechanism(s) of disease in SRP will define the components of the cilia that are most important in skeletal development. Through our main ascertainment vehicle, the International Skeletal Dysplasia Registry (ISDR), we have assembled a large cohort of SRP cases that will support a genomic strategy for genetically dissecting this disorder. The gene discovery studies will be followed by detailed mechanistic studies in tissues, cultured cells and mice to determine how each mutation exerts its phenotypic effect, to determine why mutations in the SRP genes have a differential effect on the skeleton, and to integrate the different molecules involved into a pathway for ciliary function in the skeleton. The findings will provide new insights into the complex biology of the skeleton, and will do so in the context of the SRP human phenotype. The proposed experiments are significant in that they represent the potential to have an extensive impact on our understanding of ciliary skeletal biology from both the mechanistic and clinical genetics perspectives. Once the associated genes are identified, immediate translational benefit will result by providing specific and appropriate genetic counseling to families with these conditions as well as opportunities for genetic testing. The results will reveal new molecules and mechanisms of normal skeletal development, and the proposed functional studies will both validate the molecular findings and identify the pathways through which cilia enable skeletogenesis.

 描述（由申请人提供）：基因组测序正在彻底改变我们对骨骼生物学的理解。通过确定骨骼发育不良的分子基础，一组对骨骼具有深远影响的异质遗传性疾病、正常骨骼发育所必需的意外分子和机制正在被揭示。虽然与大多数常见骨骼发育不良相关的基因已被确定，但短肋多指畸形 (SRP) 是最常见的围产期致命性骨骼疾病 其生物学基础和机制尚不完全清楚。 SRP 也是最常见的骨骼纤毛病，因此确定 SRP 疾病的分子基础和机制将确定在骨骼发育中最重要的纤毛成分。通过我们的主要确定工具——国际骨骼发育不良登记处 (ISDR)，我们收集了大量 SRP 病例，这些病例将支持从基因角度剖析这种疾病的基因组策略。基因发现研究之后将在组织、培养细胞和小鼠中进行详细的机制研究，以确定每种突变如何发挥其表型效应，确定为什么 SRP 基因突变对骨骼有不同的影响，并将涉及纤毛功能的不同分子整合到一条通路中。 在骨骼中。这些发现将为骨骼的复杂生物学提供新的见解，并将在 SRP 人类表型的背景下进行。所提出的实验具有重要意义，因为它们代表了从机械和临床遗传学角度对我们对睫状骨骼生物学的理解产生广泛影响的潜力。一旦确定了相关基因，通过向患有这些疾病的家庭提供具体和适当的遗传咨询以及基因检测的机会，将立即产生转化效益。结果将揭示正常骨骼发育的新分子和机制，拟议的功能研究将验证分子发现并确定纤毛实现骨骼发生的途径。