Therapeutic Potentials of a New Long Noncoding RNA in Diabetic Bone Wound Repair

新型长非编码 RNA 在糖尿病骨伤口修复中的治疗潜力

• 批准号: 10684848
• 负责人: JAKE JINKUN CHEN
• 金额: $ 58.9万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684848
• 关键词: Antidiabetic Drugs; Binding Proteins; Biocompatible Materials; Biological Process; Biology; Biomechanics; Blood Glucose; Bone Diseases; Bone Regeneration; Bone Resorption; Bone Tissue; Boston; Calcitonin; Cell physiology; Cellular biology; Chondrocytes; Clinic; Clinical Trials; Code; Coin; Complication; Data; Defect; Development; Diabetes Mellitus; Diabetic mouse; Disease; Dose; Drug Delivery Systems; Drug Targeting; Epidemic; Epigenetic Process; Experimental Pathology; Family; Foundations; Functional disorder; Future; Gene Expression; Genes; Health; Hyperglycemia; Impaired wound healing; Incidence; Knockout Mice; Laboratories; Length; Link; Lysine; Methods; Molecular; Molecular Biology; Mus; Natural regeneration; New Jersey; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Osteoblasts; Osteoclasts; Osteogenesis; Outcome; PTH gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Play; RNA; RNA Binding; Research; Research Personnel; Role; Selective Estrogen Receptor Modulators; Site; System; Techniques; Technology; Therapeutic; Therapeutic Effect; Transcript; Transcription Process; Universities; Untranslated RNA; bisphosphonate; bone; bone cell; bone fracture repair; bone healing; bone metabolism; cell type; diabetic; diabetic bone disease; efficacy evaluation; fracture risk; histone methylation; human disease; knockout gene; lipid biosynthesis; loss of function; mouse model; nanoparticle; new therapeutic target; novel; osteogenic; pharmacologic; posttranscriptional; prevent; recruit; side effect; skills; therapeutic RNA; therapeutic target; therapeutically effective; tissue repair; translational study; wound healing

Patients with type 2 diabetes (T2D) have substantially higher incidence of bone disorders, including as much as a 64% greater risk of fracture as compared to those without T2D. High blood glucose levels adversely alter bone cell functions, causing decreased bone formation and delayed wound healing with poor quality tissue repair. Therefore, diabetic bone disease (DBD) is a serious health concern for more than 40 million people in the US and 370 million in the world currently afflicted with T2D. Current treatments for DBD include anti-resorptive drugs, selective estrogen receptor modulators, and anabolic (bone-forming) drugs. However, these drugs target either the bone-formation or bone-resorption pathway, not both. Moreover, these drugs have little direct effect on diabetic hyperglycemia, a major root cause of T2D bone disorders. Furthermore, recent data indicate some anti-diabetic drugs have side effects that actually increase fracture risk in T2D. Therefore, developing a safe and effective method to prevent DBD and restore and regenerate lost bone tissue in diabetics is critically important. Long noncoding RNAs (lncRNAs) are a family of non-protein-coding transcripts with length longer than 200 nucleotides. Emerging evidence suggests that lncRNAs play important roles in gene expression and are involved the pathogenesis of many human diseases. Currently, there are over 60 clinical trials using lncRNAs as a remedy. Our laboratory has recently identified and initially characterized a specific lncRNA that promotes osteogenesis and inhibits adipogenesis in diabetes. It can recruit KDM6B and KDM4B and influence the histone methylation of relevant genes. Its deficiency causes bone abnormalities and retards bone regeneration and delays wound healing in mouse models. This newly discovered lncRNA is therefore coined “lncR-DBD”, suggesting its potential roles in targeting the pathophysiology of diabetic bone disease. We have successfully generated a lncR-DBD gene knockout mouse line which will enable us to further dissect the biological function of this new lncRNA. Aim 1 will determine the cellular localization of lncR-DBD and explore the epigenetic pathways using the state-of-the-art approaches; Aim 2 will define the mechanisms and alterations in bone phenotype in lncR-DBD knockout mice; Aim 3 will use a novel nanohydrogel delivery system to investigate the therapeutic effects of lncR-DBD on bone wound repair and fracture healing in diabetic mice. The outcome of our study will provide a paradigm shift in current understanding of the pathophysiology of DBD and have a significant impact on the future treatment of this epidemic disease. Firstly, building on our preliminary findings that lncR-DBD plays a pivotal role in bone metabolism, this project will further reveal novel epigenetic mechanisms of DBD. Secondly, we will decipher the pathways of lncR-DBD modulating genes in the diabetic microenvironment, which will lead to discovery of new therapeutic targets. Finally, we will deliver the lncR-DBD mimics using a novel nanohydrogel system as a safe, effective means for lncRNA-based therapy. An interdisciplinary team of investigators with complementary and synergistic skills will conduct the studies.

2型糖尿病患者（T2D）患有骨骼疾病的事件较高，包括AS 与没有T2D的裂缝相比，骨折风险大约增加了64％。高血糖水平不利 改变骨细胞功能，导致骨形成减少，质量较差的伤口愈合延迟 组织修复。因此，糖尿病骨病（DBD）是超过4000万的严重健康问题 美国的人们和世界上的3.7亿人目前遭受了T2D的困扰。目前对DBD的治疗 抗高温药物，选择性雌激素受体调节剂和合成代谢（骨形成）药物。然而， 这些药物靶向骨形成或骨吸附途径，而不是两者兼而有之。而且，这些药物有 对糖尿病性高血糖的直接影响很少，这是T2D骨骼疾病的主要根本原因。此外，最近的数据 表明某些抗糖尿病药物的副作用实际上会增加T2D的断裂风险。所以， 开发一种安全有效的方法，以防止DBD，恢复和再生糖尿病患者损失的骨组织 至关重要。长的非编码RNA（LNCRNA）是一个非蛋白质编码转录本的家族 超过200个核苷酸。新兴的证据表明，lncRNA在基因表达中起重要作用 并涉及许多人类疾病的发病机理。目前，有60多次临床试验使用 lncrnas是一种提醒。我们的实验室最近已经确定并最初表征了特定的lncRNA 促进成骨，并抑制糖尿病中的脂肪形成。它可以招募KDM6B和KDM4B并影响 相关基因的组蛋白甲基化。它的缺乏会导致骨骼异常并延迟骨骼 在小鼠模型中再生和延迟伤口愈合。因此，创造了这个新发现的lncrna “ LNCR-DBD”，表明其在靶向糖尿病骨病的病理生理学中的潜在作用。我们有 成功产生了LNCR-DBD基因敲除鼠标系，这将使我们能够进一步剖析 这种新的lncRNA的生物学功能。 AIM 1将确定LNCR-DBD的细胞定位并探索 使用最新方法的表观遗传途径； AIM 2将定义机制和更改 在LNCR-DBD敲除小鼠中的骨表型中； AIM 3将使用一种新型的纳米水凝胶输送系统 研究LNCR-DBD对糖尿病小鼠骨伤口修复和骨折愈合的治疗作用。 我们研究的结果将在当前对DBD的病理生理学的理解和 对这种流行病的未来治疗有重大影响。首先，建立我们的初步 LNCR-DBD在骨骼代谢中起关键作用的发现，该项目将进一步揭示新的表观遗传 DBD的机制。其次，我们将破译糖尿病中LNCR-DBD调节基因的途径 微环境将导致发现新的治疗靶标。最后，我们将交付LNCR-DBD 使用新型的纳米水合凝胶系统作为基于LNCRNA的治疗的一种安全，有效的手段进行模仿。一个 具有完整和协同技能的调查人员跨学科团队将进行研究。