The role of non-coding RNAs in skeletal development and disease

非编码RNA在骨骼发育和疾病中的作用

• 批准号: 211806425
• 负责人: Professor Dr. Bernhard Zabel
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/211806425?language=en
• 关键词: role; non; coding; RNAs; skeletal

The ribonuclease mitochondrial RNA-processing (RMRP) gene encodes the RNA component of a multiprotein-RNA complex termed RNase MRP. The RNase MRP complex is implicated in various cellular processes, as diverse as ribosomal biogenesis, mitochondrial RNA cleavage, cell cycle regulation, and possibly telomerase function. Mutations in the RMRP gene are the cause of the condition Cartilage Hair Hypoplasia, the first human disease known to be caused by mutations in a non-coding RNA molecule (CHH, MIM #250250). CHH is a rare autosomal recessive condition characterized by short stature and highly variable extraskeletal features, including immunodeficiency and a predisposition to malignancy. Although short stature is the leading CHH symptom, the functional role of RMRP in skeletal development remains unknown. Within the proposed research programme, we aim to unravel the mechanisms by which RMRP gene mutations cause CHH. Main specific objectives of our work plan are to determine the physiological RNase MRP function in endochondral ossification and the molecular consequences of disease-associated RMRP mutations in chondrogenic cellular systems, patient-derived primary cells and conditional mouse lines. Based on results obtained from these CHH disease models, our long-term goal is to identify novel therapeutic options. As the role of non-coding RNAs in skeletogenesis and bone disorders is a largely unexplored scientific area, our project will contribute to the development of a novel research field.

核糖核酸酶线粒体RNA加工（RMRP）基因编码称为RNase MRP的多蛋白-RNA复合物的RNA成分。RNase MRP复合物与多种细胞过程有关，如核糖体生物发生、线粒体RNA切割、细胞周期调节以及可能的端粒酶功能。RMRP基因的突变是软骨毛发发育不全的原因，这是已知的第一种由非编码RNA分子突变引起的人类疾病（CHH, MIM #250250）。CHH是一种罕见的常染色体隐性遗传病，其特征是身材矮小和高度可变的骨骼外特征，包括免疫缺陷和易患恶性肿瘤。虽然身材矮小是CHH的主要症状，但RMRP在骨骼发育中的功能作用尚不清楚。在提出的研究计划中，我们的目标是揭示RMRP基因突变导致CHH的机制。我们工作计划的主要具体目标是确定RNase MRP在软骨内成骨中的生理功能，以及软骨细胞系统、患者源性原代细胞和条件小鼠系中疾病相关RMRP突变的分子后果。基于这些CHH疾病模型获得的结果，我们的长期目标是确定新的治疗方案。由于非编码rna在骨骼形成和骨骼疾病中的作用在很大程度上是一个未开发的科学领域，我们的项目将有助于一个新的研究领域的发展。