Role of miR-17-92 miRNAs in skeletal development and bone homeostasis

 描述（由申请人提供）：微小RNA（miRNAs）在多种类型的骨骼细胞中发挥关键的调节作用。尽管越来越多的证据表明miRNA参与骨骼发育和体内平衡的多个过程，但个体miRNA在体内的具体作用在很大程度上是未知的。miR-17-92 miRNA在干/祖细胞中大量表达，并通过促进增殖和抑制分化参与其维持。miR-17-92簇miRNAs是迄今为止唯一被证明其基因突变会导致人类先天性骨骼疾病的miRNAs; miR-17-92基因的重复会导致大头畸形和手指畸形，而其杂合缺失会导致以大头畸形和短并指为特征的Feingold综合征II。此外，我们还发现miR-17- 92 miRNAs负调控小鼠成骨细胞分化和骨量。然而，miR-17-92 miRNA调控骨骼发育和骨稳态的机制尚不清楚。由于miR-17-92 miRNA预计靶向2,000多个基因，因此确定关键的分子机制是一个挑战。另一方面，据推测，生理学上重要的miRNA-RNA相互作用是进化选择的，以控制某些生物过程和途径，因为已经报道miR-17-92 miRNA以细胞环境依赖性方式调节几种信号传导途径。基于这些发现，我们假设miR-17-92 miRNA调节骨骼干/祖细胞中的关键信号通路以控制其增殖和分化，从而调节骨发育和骨稳态。为了验证这一假设，我们将首先建立小鼠模型，以确定miR-17-92 miRNA在体内组织和细胞水平上骨骼发育和出生后骨稳态中的作用。然后，我们将在miRNA-RNA相互作用、基因表达和信号通路的水平上剖析介导miR-17-92 miRNAs作用的分子机制。该项目将明确miR-17-92 miRNA在骨骼发育和骨稳态过程中骨骼干/祖细胞中的作用和作用机制，并为开发miR-17-92相关疾病和常见骨骼疾病（如骨质疏松症）的新治疗策略提供基础。

 DESCRIPTION (provided by applicant): microRNAs (miRNAs) play critical regulatory roles in multiple types of skeletal cells. Despite the accumulating evidence for miRNAs' involvement in multiple processes of skeletal development and homeostasis, specific roles of individual miRNAs in vivo are largely unknown. miR-17-92 miRNAs are abundantly expressed in stem/progenitor cells and are implicated in their maintenance by promoting proliferation and suppressing differentiation. miR-17-92 cluster miRNAs are so far the only miRNAs whose genetic mutations have been demonstrated to cause human congenital skeletal diseases; duplications of the miR-17-92 gene cause macrocephaly and digit abnormalities, whereas its heterozygous deletions result in Feingold syndrome II that is characterized by macrocephaly and brachysyndactyly. In addition, we have also found that miR-17- 92 miRNAs negatively regulate osteoblast differentiation and bone mass in mice. However, the mechanisms by which miR-17-92 miRNAs regulate skeletal development and bone homeostasis are unknown. Because miR-17-92 miRNAs are predicted to target more than 2,000 genes, identifying critical molecular mechanisms is a challenge. On the other hand, it is presumed that physiologically important miRNA-RNA interactions are evolutionarily selected to control certain biological processes and pathways, as miR-17-92 miRNAs have been reported to regulate several signaling pathways in a cellular context dependent manner. Based on these findings, we hypothesize that miR-17-92 miRNAs regulate key signaling pathways in skeletal stem/progenitor cells to control their proliferation and differentiation, and thus regulate skeleta development and bone homeostasis. To test this hypothesis, we will first generate mouse models to define the role of miR-17-92 miRNAs in skeletal development and postnatal bone homeostasis at the tissue and cellular levels in vivo. We will then dissect molecular mechanisms that mediate miR-17-92 miRNAs' action at the levels of miRNA-RNA interaction, gene expression, and signaling pathways. This project will define the role and mechanisms of action of miR-17-92 miRNAs in skeletal stem/progenitor cells during skeletal development and bone homeostasis and will provide the basis for developing new therapeutic strategies for miR-17-92-related diseases and for common skeletal diseases such as osteoporosis.