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（由申请人提供）：我们将研究一种新型的microRNA（miR）介导的遗传途径，这对于正常的颅面发育至关重要。 microRNA是小的非编码RNA，在转录后抑制基因表达。使用小鼠和染色质免疫沉淀（CHIP）中的条件失活，我们最近报道了MiR17-92簇是心脏祖细胞中BMP信号传导的直接靶标。我们的初步数据表明，miR17-92突变体胚胎具有严重的颅面表型，包括唇裂和pa裂（Cl/p）和下颌骨发育不全，这与Mir17-92是颅型形成形成中的MiR17-92是BMP-target的假设。这是第一个遗传证据，即单个miR或miR簇在哺乳动物CL/p中在功能上很重要。重要的是，MiR17-92位于与13Q缺失综合征相关的关键区域的人类染色体13q31.3上。此外，miR17-92簇与乳腺癌，视网膜细胞瘤和淋巴瘤等人类癌症有关，表明对miR17-92功能的洞察力具有广泛的人类健康影响。我们最近发表的发现表明，MiR17- 92通过下调祖细胞基因（例如Digeorge/Velo-Cardio-Facio-Facial综合征（DGS）基因，TBX1，在从祖细胞到分化的CLL的过渡中起关键作用。我们的初步数据表明，miR17-92还抑制尺乳腺综合征（UMS）基因TBX3。我们建议在开发颅面结构中严格研究MIR17-92受调节的途径：在特定的目标1：我们将研究MiR17-92抑制Tbox转录调节剂TBX3的假设，以调节唇部和papal发育。在特定目标2中：我们将测试以下假设：MiR17-92通过精确调节TBX1表达水平是TBX1的遗传修饰符。在特定的目标3中，我们将研究以下假设：TBX1和TBX3中的miR17-92种子位点直接抑制体内中心发育过程中TBX1和TBX3时空表达。对Cl/p的遗传机制的理解不足。新的遗传见解对于将来的诊断测试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扎实的科学信息来制定新的治疗策略，这些信息将来自模型生物体和人类遗传学的工作。