Nanolipidoids-Conjugated MicroRNA Enhance Oral and Cranial Bone Regeneration

纳米脂质结合的 MicroRNA 增强口腔和颅骨再生

基本信息

批准号：
9106764
负责人：
JAKE JINKUN CHEN
金额：
$ 33万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9106764
关键词：
Adverse effects Anatomy Animal Model Animals Biological Biological Process Bone Diseases Bone Marrow Bone Matrix Bone Regeneration Bone Tissue Cells Cephalic Clinical Clinical Treatment Clinical Trials Defect Deformity Drug Targeting Engineering Failure Fracture Fracture Healing Future Genes Genome Hepatitis C Implant In Situ Individual Joints Label Laboratories Lead Life Malignant Neoplasms Mammalian Cell Mesenchymal Stem Cells MicroRNAs Molecular Mus Muscle Natural regeneration Nerve Operative Surgical Procedures Oral Organ Transplantation Osseointegration Osteoblasts Osteogenesis Osteoporosis Patients Periodontitis Phase Physiological Positioning Attribute Procedures Regenerative Medicine Signal Transduction Site Stromal Cells System Testing Therapeutic Therapeutic Agents Tissue Engineering Tissues Transcript Transgenes Transgenic Animals Transgenic Mice Translational Research Transplantation Untranslated RNA Untranslated Regions Viral Vector Work Wound Healing adult stem cell angiogenesis base beta catenin bone bone mass clinical application cost craniofacial experience human disease in vivo induced pluripotent stem cell innovation interest mouse genome nanomaterials nanoparticle novel organ growth osteogenic osteogenic protein overexpression physical property preclinical trial promoter public health relevance scaffold skills stem cell biology stem cell differentiation success therapeutic miRNA therapeutic target tissue regeneration transcription factor translational study wound

项目摘要

DESCRIPTION (provided by applicant): While over 500,000 surgeries correcting bone deformities and critical size defects occur each year in the US, 50% of the procedures end in failure. Therefore, using molecular engineering approaches to regenerate lost bone with normal anatomic contour, physical properties and biological function is of enormous importance. MicroRNAs (miRNAs) are non-coding RNAs that are emerging as new and powerful drug targets. Currently there are 157 preclinical and clinical trials of miRNA-based therapeutics. We have identified a novel miRNA, miR-335-5p, which targets the 3'-UTR sequence of DKK1, a Wnt signal antagonist, and down-regulates DKK1 expression. We also revealed that miR-335-5p is an important regulator for osteogenic differentiation. We have further generated a transgenic mouse line in which miR-335-5p gene is overexpressed in bone tissue showing enhanced expression of marker genes and increased bone mass accrual. Based on these interesting findings we plan to use miR-335-5p as a therapeutic target to enhance oral and craniofacial bone regeneration using our newly synthesized and characterized lipidoid-miRNA nanoparticles as a novel delivery vehicle. Aim 1. We will determine regulatory and osteogenic effects of miR-335-5p overexpression in bone regeneration and wound repairing using a transgenic animal model. Our hypothesis is that since miR-335-5p transgene is incorporated into mouse genome its super-physical transcript levels will boost the bone forming capacity in target cells. Aim 2. We will develop two therapeutic strategies with a nanoparticle lipidoid system to deliver miR-335-5p molecules in vivo for oral and craniofacial bone regeneration. Firstly, we will transplant miR-335-5p-modified bone marrow stromal cells into bone wound site to enhance bone formation. Our hypothesis is that miR-335-5p specifically suppresses DKK1 and activates Wnt/β−Catenin signals, which further triggers an osteogenic cascade leading BMSC differentiation towards osteoblastic lineage and an increased bone formation capability. Secondly, we will determine the effect of miR-335-5p in promoting bone-forming cells in situ and enhancing wound healing and tissue regeneration. Our hypothesis is that local administration of miR-335-5p in wound site directly leads mesenchymal stem cells differentiation into bone forming cells, accelerating wound healing and bone regeneration. This translational research will explore the potential of miR-335-5p as a therapeutic agent for promoting bone regeneration and wound healing. This innovative miRNA-based therapy has potential for the clinical treatment of other bone disorders including osteoporosis, fracture, periodontitis and impaired osseointegration of bone/joint implants.

描述（由申请人提供）：虽然美国每年发生超过 500,000 例矫正骨骼畸形和临界尺寸缺陷的手术，但其中 50% 的手术以失败告终。因此，使用分子工程方法来再生具有正常解剖轮廓、物理特征的丢失骨骼。 MicroRNA (miRNA) 是非编码 RNA，目前有 157 个临床前和临床药物靶点。我们已经鉴定了一种新的 miRNA，miR-335-5p，它靶向 Wnt 信号拮抗剂 DKK1 的 3'-UTR 序列，并下调 DKK1 的表达。 -5p 是成骨分化的重要调节因子，我们进一步培育了一种转基因小鼠品系，其中 miR-335-5p 基因在骨组织中过度表达，显示出标记基因表达增强和骨量增加。基于这些有趣的发现，我们计划使用 miR-335-5p 作为治疗靶点，使用我们新合成和表征的类脂质-miRNA 纳米颗粒作为新型递送载体来增强口腔和颅面骨再生。使用转基因动物模型研究 miR-335-5p 过表达对骨再生和伤口修复的调节和成骨作用，我们的假设是，由于 miR-335-5p 转基因是将其超物理转录水平纳入小鼠基因组将增强靶细胞的骨形成能力。目标 2。我们将开发两种利用纳米颗粒类脂质系统的治疗策略，在体内递送 miR-335-5p 分子，用于口腔和颅面骨再生。首先，我们将 miR-335-5p 修饰的骨髓基质细胞移植到骨伤口部位以增强骨形成。我们的假设是 miR-335-5p 特异性抑制 DKK1。并激活 Wnt/β−Catenin 信号，进一步触发成骨级联反应，导致 BMSC 向成骨细胞分化，并增强骨形成能力。其次，我们将确定 miR-335-5p 在原位促进骨形成细胞中的作用。我们的假设是，在伤口部位局部施用 miR-335-5p 直接导致间充质干细胞分化为骨形成细胞，从而加速伤口愈合和骨再生。这项转化研究将探索 miR-335-5p 作为促进骨再生和伤口愈合的治疗剂的潜力，这种基于 miRNA 的创新疗法具有临床治疗其他骨疾病的潜力，包括骨质疏松症、骨折、牙周炎和骨整合受损。骨/关节植入物。