Alveolar Bone Regeneration in Diabetic Periodontitis

糖尿病牙周炎的牙槽骨再生

基本信息

批准号：
10058838
负责人：
JAKE JINKUN CHEN
金额：
$ 39.19万
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：
2016-12-12 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058838
关键词：
Adult Affinity Agonist Alveolar Bone Loss American Anti-Inflammatory Agents Antidiabetic Drugs Binding Blood Blood Glucose Bone Diseases Bone Formation Inhibition Bone Regeneration Bone Resorption Cell Differentiation process Cells Cellular Metabolic Process Chemicals Defect Diabetes Mellitus Diabetic mouse Disadvantaged Disease Dose Frequencies Gene Expression Genes Glucose Intolerance Goals Hyperglycemia Impairment Infiltration Inflammation Inflammatory Injections Insulin Resistance Investigation Knock-out Knockout Mice Label Literature Longevity Measurement Measures Mediator of activation protein Mesenchymal Stem Cells Metabolic Methods Modeling Molecular Natural regeneration Nature Non-Insulin-Dependent Diabetes Mellitus Oral Osteoblasts Osteoclasts Osteogenesis Pathology Pattern Periodontal Diseases Periodontitis Phenotype Population Property Proteins Refractory Role Sampling Severities Signal Pathway Signal Transduction Signal Transduction Pathway Site Specificity Stromal Cell-Derived Factor 1 Therapeutic Therapeutic Agents Therapeutic Effect Time Tooth structure Translational Research adipokines adiponectin aged alveolar bone base bone bone cell bone healing clinical application diabetic diabetic patient drug development fluorexon healing immunoreaction insight insulin sensitizing drugs microCT migration mouse model non-diabetic novel novel therapeutics osteoblast differentiation osteoclastogenesis osteogenic preservation receptor recruit repaired small molecule stem cell migration stem cells wound

项目摘要

Over 47% of American adults aged 30 and over have periodontitis. Further, periodontitis is twice as prevalent in diabetics as in non-diabetics, and type 2 diabetes (T2D) currently afflicts 40 million Americans. T2D-associated periodontitis is severe and, in many cases, refractory to current treatments due to the altered and aberrant functions of bone cells in hyperglycemic conditions. Therefore, developing an effective method to restore and regenerate lost alveolar bone to reserve the natural teeth in diabetics is critically important. Adiponectin, an adipokine, has anti-inflammatory and anti-diabetic properties. We have found that adiponectin inhibits differentiation and activity of osteoclasts and significantly decreases alveolar bone loss. At the same time, it promotes the osteoblast niche and mesenchymal stem cell migration, and enhances bone defect healing. However, adiponectin protein-based therapy has disadvantages that limit its clinical application, including adverse immunoreactions and the need for constant IV injection of high doses for therapeutic effect. An adiponectin receptor agonist, AdipoRon (APR) was recently identified (Nature 503:493-9, 2013), which can be orally administrated to ameliorate insulin resistance and glucose intolerance, and prolong the shortened lifespan of diabetic mice. Our preliminary studies indicate that APR upregulates expression and activity of adiponectin receptors exerting favorable effects on bone cell metabolism. Our purpose is to use APR, a small molecule chemical compound, as a novel therapeutic agent to effectively treat diabetic periodontitis. Our central hypothesis is that, in addition to systemically controlling hyperglycemia and inflammation, APR directly triggers molecular signals that correct the imbalance of bone resorption and formation, reversing pathology and promoting regeneration of lost alveolar bone, and allowing the natural teeth to be reserved. In Aim 1 we will first determine the affinity and efficacy of APR binding to adiponectin receptors in bone cells, initiation of downstream signal mediator expression, and enhancement of bone formation. To verify the specificity and affinity of the interaction between this novel exogenous agonist and endogenous receptor, we will use receptor knock out mice. In Aim 2 we will delineate the APR effect in ameliorating and correcting diabetic 'mobilopathy' - in which cell differentiation, recruitment and migration are seriously impaired in diabetes. We will use an adiponectin knock out mouse line to determine if APR can effectively surrogate adiponectin in promoting the necessary microenvironment and deploying sufficient bone forming cells to regenerate alveolar bone damaged in periodontitis. In Aim 3 we will generate experimental periodontitis in a mouse model of diabetes to further determine the overall effects of APR in reducing hyperglycemia and inflammation as well as its anabolic effect for periodontal bone regeneration. This translational research will yield initial characterization of a novel therapeutic agent with strong potential for treating diabetic periodontal disease and provide baseline information for drug development for treating periodontitis and other bone diseases associated with diabetes.

超过47％的30岁及以上的美国成年人患有牙周炎。此外，牙周炎是与非糖尿病患者一样，在糖尿病患者中普遍存在，目前遭受了4000万美国人的痛苦，2型糖尿病（T2D）。 T2D相关的牙周炎很严重，在许多情况下，由于改变了当前治疗在高血糖条件下骨细胞的异常功能。因此，开发一种有效的方法来恢复和再生肺泡骨骼以保留糖尿病患者的天然牙齿至关重要。脂联素是一种脂肪因子，具有抗炎和抗糖尿病特性。我们发现脂联素抑制破骨细胞的分化和活性，并显着降低肺泡骨质流失。同样时间，它可以促进成骨细胞和间质干细胞迁移，并增强骨缺损愈合。但是，脂联素蛋白质的疗法的缺点可以限制其临床应用，包括不良免疫反应以及需要恒定的IV注射高剂量以进行治疗作用。一个最近确定了脂联素受体激动剂（APR）（APR）（自然503：493-9，2013），可以是口服以改善胰岛素抵抗和葡萄糖不耐受，并延长缩短糖尿病小鼠的寿命。我们的初步研究表明，APR上调脂联素受体对骨细胞代谢产生有利作用。我们的目的是使用APR，一个小分子化合物，是一种有效治疗糖尿病牙周炎的新型治疗剂。我们的中心假设是，除了系统地控制高血糖和炎症外，APR直接触发纠正骨吸收和形成不平衡的分子信号，逆转病理和促进失去肺泡骨的再生，并保留天然牙齿。在目标1中，我们将首先确定APR与骨细胞中脂联素受体结合的亲和力和功效下游信号介体表达和骨形成的增强。验证特异性和这种新型的外源激动剂和内源性受体之间相互作用的亲和力，我们将使用受体淘汰老鼠。在AIM 2中，我们将描述改善和纠正糖尿病“动员”的APR效应 - 在糖尿病中，细胞分化，募集和迁移严重受损。我们将使用脂联素敲除小鼠系，以确定APR是否可以有效替代脂联素在促进必要的微环境和部署足够的骨形成细胞以再生牙槽损坏在牙周炎中。在AIM 3中，我们将在糖尿病小鼠模型中产生实验性牙周炎，以进一步确定APR在减少高血糖和炎症及其合成代谢作用中的总体影响用于牙周骨再生。这项翻译研究将产生新颖的初始特征具有强大潜力治疗糖尿病牙周疾病并提供基线信息的治疗剂用于治疗牙周炎和与糖尿病有关的其他骨骼疾病的药物开发。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Identification and characterization of a novel adiponectin receptor agonist adipo anti-inflammation agonist and its anti-inflammatory effects in vitro and in vivo.

DOI：
10.1111/bph.15277
发表时间：
2021-01
期刊：
British journal of pharmacology
影响因子：
7.3
作者：
Qiu W;Wu H;Hu Z;Wu X;Tu M;Fang F;Zhu X;Liu Y;Lian J;Valverde P;Van Dyke T;Steffensen B;Dong LQ;Tu Q;Zhou X;Chen J
通讯作者：
Chen J

Osteogenic effects of microRNA-335-5p/lipidoid nanoparticles coated on titanium surface.

DOI：
10.1016/j.archoralbio.2021.105207
发表时间：
2021-09
期刊：
Archives of oral biology
影响因子：
3
作者：
Wang Q;Wang X;Valverde P;Murray D;Dard MM;Van Dyke T;Xu Q;Xu X;Karimbux N;Tu Q;Chen J
通讯作者：
Chen J

Overexpression of MiR-335-5p Promotes Bone Formation and Regeneration in Mice.

DOI：
10.1002/jbmr.3230
发表时间：
2017-12
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
0
作者：
Zhang L;Tang Y;Zhu X;Tu T;Sui L;Han Q;Yu L;Meng S;Zheng L;Valverde P;Tang J;Murray D;Zhou X;Drissi H;Dard MM;Tu Q;Chen J
通讯作者：
Chen J

AdipoRon promotes diabetic fracture repair through endochondral ossification-based bone repair by enhancing survival and differentiation of chondrocytes.