Roles of Noncoding RNA in Bone Regeneration

非编码 RNA 在骨再生中的作用

• 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
• 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' 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

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).

此次续签补助金申请代表了当前补助金 (DE25681) 的深化扩展，重点关注 关于 microRNA (miR)-335-5p 的骨增强作用，该作用首次在我们的实验室中鉴定和表征。我们 发表了9篇以上同行评审论文，并在报告结果方面获得了多项奖项和奖项。我们有 最近报道了我们关于miR-335-5p抑制破骨细胞分化和骨功能的新发现 吸收。我们进一步发现miR-335-5p通过与3’UTR元件结合发挥抑制作用 igsf3（免疫球蛋白超家族，成员 3）的成员。 Igsf3在破骨细胞过程中表达增加 分化与miR-335-5p的表达呈负相关。这一新发现与 miR-335-5p 的良好表征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病的候选药物，其中之间的平衡 骨形成和吸收受到干扰。目前，骨质疏松症的治疗方法包括抗骨吸收药物 和合成代谢骨形成药物。然而，这些药物要么针对骨吸收，要么针对骨形成。 途径，但不是两者兼而有之。许多基于蛋白质的疗法都存在副作用和高风险等缺点。 成本。我们已经生成了 miR-335-5p 基因敲除（功能丧失）和过度表达 （功能获得）小鼠。这两个鼠标系列将提供最先进和最复杂的方法 进行基因操作以达到我们的研究目的。与科学家和生物工程师合作 新泽西理工学院，我们开发了新颖且尖端的靶向纳米粒子 首次将miR-335-5p精准递送至靶细胞，发挥双效作用 骨吸收和骨形成途径。目的 1. 探索新的分子机制 发现miR-335-5p具有抑制破骨细胞活性和骨吸收的功能；目标 2. 使用我们的 新生成的 miR-335-5p 基因敲除和过表达小鼠来表征多层功能 miR-335-5p 在骨代谢中的作用；目标 3. 应用新开发的靶向纳米粒子来递送 miR-335-5p 对特定细胞类型的影响，并确定其对骨伤口愈合和逆转的治疗作用 骨质疏松症。我们将确定给定有效浓度、最佳浓度的 miR-335-5p 的治疗效果 频率和准确的给药持续时间，以最大限度地发挥其在细胞和组织方面的功能 水平。这个更新项目在概念上、技术上和干预上都是创新的。有利的 基于 miRNA 的疗法的特点将使这项转化研究改变理解范式， 治疗并最终治愈骨质疏松症及其相关的骨骼疾病。跨学科团队 具有互补和协同技能的研究人员将进行研究（Jake Chen – 实验 病理学和骨生物学；涂启胜——细胞与分子生物学；徐晓阳 – 生物材料与药物 送货）。