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 (T2D) 患者的骨疾病发生率明显更高，包括 与没有患 T2D 的人相比，高血糖水平会增加 64% 的骨折风险。 改变骨细胞功能，导致骨形成减少和伤口愈合延迟且质量差 因此，糖尿病骨病 (DBD) 是超过 4000 万人的严重健康问题。 目前，美国和全球有 3.7 亿人患有 T2D，目前治疗 DBD 的方法包括： 抗再吸收药物、选择性雌激素受体调节剂和合成代谢（骨形成）药物。 这些药物针对骨形成或骨吸收途径，而不是同时针对两者。 对糖尿病高血糖几乎没有直接影响，而糖尿病高血糖是 T2D 骨病的一个主要原因。此外，最近的数据显示。 表明一些抗糖尿病药物的副作用实际上会增加 2 型糖尿病的骨折风险。 开发一种安全有效的方法来预防 DBD 并恢复和再生糖尿病患者丢失的骨组织 长非编码 RNA (lncRNA) 是具有长度的非蛋白质编码转录物家族。 超过200个核苷酸的新证据表明lncRNA在基因表达中发挥重要作用。 并涉及许多人类疾病的发病机制，目前有超过60项临床试验在使用。 lncRNA 作为一种治疗方法，我们的实验室最近发现并初步表征了一种特定的 lncRNA，它可以 在糖尿病中促进骨生成并抑制脂肪生成。它可以募集 KDM6B 和 KDM4B 并影响。 相关基因的组蛋白甲基化会导致骨骼异常并阻碍骨骼生长。 因此，这种新发现的 lncRNA 被创造出来。 “lncR-DBD”，表明其在针对糖尿病骨病的病理生理学方面的潜在作用。 成功生成了 lncR-DBD 基因敲除小鼠品系，这将使我们能够进一步剖析 这个新的lncRNA的生物学功能将确定lncR-DBD的细胞定位并探索。 使用最先进的方法的表观遗传途径将定义机制和改变； Aim 3 将使用一种新型纳米水凝胶递送系统来改变 lncR-DBD 敲除小鼠的骨表型； 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。 我们的研究结果将为当前对 DBD 病理生理学的理解提供范式转变 对这种流行病的未来治疗产生重大影响首先，在我们的初步基础上。 研究发现lncR-DBD在骨代谢中发挥着关键作用，该项目将进一步揭示新的表观遗传学 其次，我们将破译lncR-DBD调节基因在糖尿病中的通路。 微环境，这将导致新的治疗靶点的发现，最后，我们将提供 lncR-DBD。 模仿使用新型纳米水凝胶系统作为基于 lncRNA 的治疗的安全、有效手段。 具有互补和协同技能的跨学科研究人员团队将进行研究。