Roles of Noncoding RNA in Bone Regeneration

非编码 RNA 在骨再生中的作用

基本信息

批准号：
9897297
负责人：
JAKE JINKUN CHEN
金额：
$ 65.37万
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 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9897297
关键词：
3&apos Untranslated Regions Age American Applications Grants Award Awards and Prizes Binding Biocompatible Materials Biological Biological Assay Biology Biomechanics Biomedical Engineering Bone Density Bone Diseases Bone Regeneration Bone Resorption Bone callus Cells Crossbreeding Data Disadvantaged Disease Disease model Dose Drug Delivery Systems Drug Targeting Elements Epidemic Equilibrium Experimental Pathology Femoral Fractures Foundations Fracture Healing Frequencies Functional disorder Genes Grant Hand Immunoglobulins Individual Institutes Intervention Laboratories Luciferases MMP9 gene Mature Bone Metabolic MicroRNAs Molecular Molecular Biology Mus Mutation New Jersey Osteoblasts Osteoclasts Osteogenesis Osteoporosis Ovariectomy PTH gene Paper Pathway interactions Patients Peer Review Pharmaceutical Preparations Pharmacologic Substance Pharmacy (field)Phenotype Process Progress Reports Property Proteins Publishing Reporter Reporting Research Research Personnel Research Project Grants Risk Role Scientist Selective Estrogen Receptor Modulators Signal Pathway Site System Technology Therapeutic Effect Time Transgenic Mice United States National Institutes of Health Untranslated RNA Woman base bisphosphonate bone bone metabolism cathepsin K cell type cost experience experimental study gain of function genetic manipulation improved innovation knockout gene loss of function member men nanoparticle novel osteogenic osteoporosis with pathological fracture osteoporotic bone outcome forecast overexpression regenerative side effect skills therapeutic miRNA translational study wound wound healing

项目摘要

This renewal grant application represents a deepened extension of the current grant (DE25681) focusing on the bone-enhancing effects of microRNA (miR)-335-5p, first identified and characterized in our laboratory. We have published over 9 peer-reviewed papers and won many prizes and awards in reporting the results. We have recently reported our new discovery of the function of miR-335-5p in inhibiting osteoclast differentiation and bone resorption. We further found that miR-335-5p exerts its inhibitory effect through its binding to the 3’UTR elements of igsf3 (immunoglobulin superfamily, member 3). Igsf3’s increased expression during the process of osteoclast differentiation is reversely correlated with the expression of miR-335-5p. This new discovery together with the well-characterized anabolic osteogenic effect of miR-335-5p, has led us to speculate that miR-335-5p is a potent pharmaceutical candidate for treating osteoporosis and its related bone disorders, where the balance between bone formation and resorption is disturbed. At present, osteoporosis treatments include anti-resorptive drugs and anabolic bone-forming drugs. However, these drugs target either the bone-resorption or bone-formation pathway, but not both. Many protein-based therapies have the disadvantages including side-effects and the high cost. We have generated both miR-335-5p gene knockout (loss-of-function) and overexpression (gain-of-function) mice. These two mouse lines will provide the most advanced and sophisticated approaches for gene manipulation to achieve our research purposes. Collaborating with scientists and bioengineers at the New Jersey Institute of Technology, we have developed novel and cutting-edge targeted nanoparticles for the first time to precisely deliver miR-335-5p to the target cells where it can exert its dual-effects in both bone-resorption and bone-formation pahways. Aim 1. To explore the molecular mechanism of the newly discovered function of miR-335-5p in suppressing osteoclast activity and bone resorption; Aim 2. To use our newly generated miR-335-5p gene knockout and overexpression mice to characterize the multilayered functions of miR-335-5p in bone metabolism; Aim 3. To apply newly developed targeted nanoparticles to deliver miR-335-5p to specific cell types and determine its therapeutic effects on bone wound healing and reversal of osteoporosis. We will determine the therapeutic effects of miR-335-5p given effective concentration, optimal frequency, and accurate duration of administration to maximize its functions at both cellular and organismal levels. This renewal project is conceptually, technically, and interventionally innovative. The advantageous features of miRNA-based therapy will allow this translational study to shift the paradigm in understanding, treating and ultimately curing osteoporosis and its related bone disorders. An interdisciplinary team of investigators with complementary and synergistic skills will conduct the studies (Jake Chen – experimental pathology and bone biology; Qisheng Tu – cell and molecular biology; Xiaoyang Xu – biomaterials and drug delivery).

该更新赠款申请代表了当前赠款（DE25681）的加深延长关于MicroRNA（MIR）-335-5p的骨增强作用，首先在我们的实验室中鉴定和表征。我们已经发表了9多份同行评审的论文，并在报告结果时赢得了许多价格和奖项。我们有最近报道了我们对miR-335-5p抑制破骨细胞分化和骨骼的功能的新发现解决。我们进一步发现，miR-335-5p通过与3'UTR元素的结合执行其抑制作用 IGSF3（免疫球蛋白超家族，成员3）。 IGSF3在破骨细胞过程中的表达增加分化与miR-335-5p的表达相反。这个新发现以及 miR-335-5p的良好特征化的合成代谢成骨作用，使我们推测miR-335-5p是一种有效的治疗骨质疏松症及其相关骨骼疾病的药物候选者，其中骨形成和分辨率受到干扰。目前，骨质疏松症治疗包括抗敏化药物和合成代谢骨的药物。但是，这些药物靶向骨吸或骨形成路径，但不是两者。许多基于蛋白质的疗法都有灾难，包括副作用和高成本。我们已经产生了miR-335-5p基因敲除（功能丧失）和过表达（功能收益）小鼠。这两种鼠标线将提供最先进，最复杂的方法为了实现我们的研究目的。与科学家和生物工程师合作新泽西理工学院，我们已经开发了新颖和尖端的针对性纳米颗粒第一次准确地将miR-335-5p交付给目标单元，可以在两者中执行双重效应骨吸附和骨形成Pahways。目标1。探索新近的分子机制发现miR-335-5p在抑制破骨细胞活性和骨骼分辨率中发现的功能；目标2。使用我们新生成的miR-335-5p基因敲除和过表达小鼠以表征多层功能骨代谢中的miR-335-5p；目标3。应用新开发的靶向纳米颗粒以交付 miR-335-5p至特定细胞类型，并确定其对骨伤口愈合的治疗作用骨质疏松症。我们将确定有效浓度，最佳的miR-335-5p的治疗作用频率和准确的给药持续时间以最大化其在细胞和有机体上的功能水平。这个更新项目在概念上，技术和介入方面都是创新的。有利的基于miRNA的治疗的特征将使这项翻译研究能够改变理解范式，治疗并最终治愈骨质疏松症及其相关的骨骼疾病。一个跨学科团队具有完整和协同技能的研究人员将进行研究（Jake Chen - 实验性病理学和骨生物学； Qisheng tu - 细胞和分子生物学； Xiaoyang Xu - 生物材料和药物送货）。