MicroRNAs in cleft lip and palate

唇裂和腭裂中的 MicroRNA

• 批准号: 8770032
• 负责人: James F Martin
• 金额: $ 56.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-04 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770032
• 关键词: 22q11.2; 3' Untranslated Regions; Alleles; Animal Model; Bacterial Artificial Chromosomes; Cardiac; Cells; Chromosomes; Cleft Palate; Confocal Microscopy; Counseling; Craniofacial Abnormalities; Data; Development; Diagnostic tests; Dose; Embryo; Engineering; Family; Future; Gene Expression; Genes; Genetic; Goals; Health; Human; Human Chromosomes; Human Genetics; Individual; Knowledge; Lip structure; Lymphoma; Malignant Neoplasms; Mandible; Mediating; MicroRNAs; Morphogenesis; Mus; Mutate; Palate; Pathway interactions; Patients; Phenotype; Play; Process; Publishing; Reporter; Reporting; Research; Resolution; Resources; Retinoblastoma; Role; Seeds; Shprintzen syndrome; Signal Transduction; Site; Solid; Structure; Testing; Transgenic Organisms; Ulnar-Mammary Schinzel Syndrome; Untranslated RNA; Untranslated Regions; Work; base; cardiogenesis; chromatin immunoprecipitation; chromosome 13q deletion syndrome; cleft lip and palate; craniofacial; craniofacial development; gain of function; human genome sequencing; in vivo; insight; loss of function; malignant breast neoplasm; mutant; novel; novel therapeutics; progenitor; research study; spatiotemporal; tool

DESCRIPTION (provided by applicant): We will investigate a novel microRNA (miR) mediated genetic pathway that is essential for normal craniofacial development. MicroRNAs are small, non-coding RNAs that repress gene expression post-transcriptionally. Using conditional inactivation in mice and chromatin immunoprecipitation (ChIP), we recently reported that the miR17-92 cluster is a direct target for Bmp signaling in cardiac progenitors. Our preliminary data indicate that miR17-92 mutant embryos have severe craniofacial phenotypes, including cleft lip and palate (CL/P) and mandibular hypoplasia, consistent with the hypothesis that miR17-92 is a Bmp-target in craniofacial morphogenesis. This is the first genetic evidence that an individual miR or miR cluster is functionally important in mammalian CL/P. Importantly, miR17-92 is located on human chromosome 13q31.3 in a critical region for cleft lip and palate associated with 13q deletion syndrome. Moreover, the miR17-92 cluster has been implicated in human cancers such as breast cancer, retinoblastoma, and lymphoma indicating that insight into miR17-92 function has broad human health implications. Our recently published findings indicate that miR17- 92 plays a critical role in the transition from progenitor to differentiated cll by downregulating progenitor genes such as the DiGeorge/velo-cardio-facial syndrome (DGS) gene, Tbx1. Our preliminary data suggest that miR17-92 also represses Tbx3, the ulnar mammary syndrome (UMS) gene. We propose to rigorously investigate the miR17-92 regulated pathways in developing craniofacial structures: In Specific Aim 1: We will investigate the hypothesis that miR17-92 inhibits the Tbox transcriptional regulator,Tbx3, to regulate lip and palate development. In Specific Aim 2: We will test the hypothesis that miR17-92, by precisely regulating Tbx1 expression levels, is a genetic modifier for Tbx1. In Specific Aim 3, we will investigate the hypothesis that miR17-92 seed sites in Tbx1 and Tbx3 directly inhibit Tbx1 and Tbx3 spatiotemporal expression during in vivo midface development. There is poor understanding of the genetic mechanisms underlying CL/P. New genetic insights will be critical for diagnostic testing and family counseling in the future. Moreover, an in depth knowledge of genetics of CL/P will provide critical resources for patient management as human genome sequencing becomes more commonplace. Finally, there is the long term goal to develop novel therapeutic strategies based on solid scientific information that will come from work in model organisms and human genetics.

描述(由申请者提供)：我们将研究一种新的microRNA(MiR)介导的遗传途径，这是正常颅面发育所必需的。MicroRNA是一种小的、非编码的RNA，它在转录后抑制基因的表达。利用小鼠条件失活和染色质免疫沉淀(ChIP)，我们最近报道了miR17-92簇是心脏祖细胞BMP信号的直接靶点。我们的初步数据表明，miR17-92突变胚胎具有严重的头面部表型，包括唇腭裂(CL/P)和下颌发育不良，这与miR17-92是头面部形态发生中的BMP靶点的假设一致。这是首次有遗传学证据表明单个miR或miR簇在哺乳动物CL/P中具有重要的功能。重要的是，miR17-92位于人类染色体13q31.3上与13q缺失综合征相关的唇腭裂的关键区域。此外，miR17-92簇已经与乳腺癌、视网膜母细胞瘤和淋巴瘤等人类癌症有关，这表明对miR17-92功能的深入了解对人类健康具有广泛的影响。我们最近发表的研究结果表明，miR17-92通过下调DiGeorge/velo心脏面部综合征(DGS)基因TBX1等前体基因在从祖细胞向分化CLL的转变过程中发挥关键作用。我们的初步数据表明，miR17-92也抑制了尺骨乳腺综合征(UMS)基因TBX3。我们建议严格研究miR17-92在颅面结构发育中的调控途径：在特定目标1：我们将研究miR17-92抑制Tbox转录调控因子TBX3调控唇腭部发育的假说。在特定目标2：我们将测试假设，即miR17-92，通过精确调控TBX1的表达水平，是TBX1的遗传修饰物。在特定的目标3中，我们将研究在活体中面发育过程中，TBX1和TBX3上的miR17-92种子位置直接抑制TBX1和TBX3的时空表达的假设。目前对CL/P的遗传机制了解甚少，新的遗传学见解将对未来的诊断检测和家庭咨询至关重要。此外，随着人类基因组测序变得越来越普遍，对CL/P遗传学的深入了解将为患者管理提供关键资源。最后，有一个长期目标是基于坚实的科学信息开发新的治疗策略，这些信息将来自模式生物和人类遗传学的工作。