Therapeutic Strategies for Treating Type 2 Diabetes Mellitus -Associated Periodon

治疗 2 型糖尿病相关牙周病的治疗策略

基本信息

批准号：
8184470
负责人：
JAKE JINKUN CHEN
金额：
$ 37.13万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-20 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8184470
关键词：
Adipocytes Adipose tissue Affect American Animal Model Anti-Inflammatory Agents Anti-inflammatory Apoptosis Biological Process Biomedical Engineering Boston Diabetes Mellitus Disease Excision Fatty acid glycerol esters Glucose Health Homeostasis Hormones Inflammation Inflammation Mediators Inflammatory Infusion procedures Insulin Insulin Resistance Interleukin-6 Knockout Mice Lesion Mediating Mediator of activation protein Mus Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Obesity Osteoclasts Osteogenesis Pathogenesis Pathway interactions Patients Periodontal Diseases Periodontitis Phenotype Physiological Plasma Proto-Oncogene Proteins c-akt Quality of life Refractory Resolution Role Severities Signal Pathway Symptoms TNF gene TNFSF11 gene Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Tissues Tooth Loss Tooth structure Universities Work adiponectin alveolar bone base bone bone metabolism diabetic experience improved in vivo insulin sensitivity loss of function mRNA Expression mouse model non-diabetic novel osteoblast differentiation osteoclastogenesis reconstruction release factor repaired tool

项目摘要

DESCRIPTION (provided by applicant): Periodontitis is twice as prevalent in diabetics as in non-diabetics. Diabetic periodontal diseases are more severe and refractory because T2DM and obesity trigger the release of excess inflammatory factors, such as TNF-1 and IL-6, which in turn stimulate osteoclasts to resorb the alveolar bone that supports the teeth. Adiponectin, a fat cell derived hormone, is emerging as a potent molecule with multiple biological functions including regulating insulin sensitivity, suppressing inflammation, and improving diabetic symptoms. It also promotes osteoblastic differentiation and bone formation. Our recent studies have shown that adiponectin inhibits osteoclast differentiation and increases osteoclast apoptosis. Our long-term objective is to identify and characterize an ideal endogenous mediator as a potent therapeutic remedy for the treatment of the widely prevalent T2DM-associated periodontitis. The objective of this application is to investigate the mechanisms of adiponectin in the pathogenesis of T2DM-associated periodontitis and to specifically reconstruct the inflammatorily damaged periodontal tissues by the replenishment of adiponectin in vivo. The central hypothesis to be tested is that the decreased level of adiponectin, together with the consequent removal of its suppressive effects on osteoclasts and proinflammatory factors, contributes to the pathogenesis of T2DM and T2DM-associated periodontitis. Also, a systemic adiponectin infusion promotes the reconstruction of the damaged periodontal tissues. Aim 1: Using an animal model for the first time to determine the effects of anti-inflammatory factor in periodontal pathogenesis including inhibition of differentiation of osteoclasts that directly resorb alveolar bone. Aim 2: To determine the therapeutic effect of systemic adiponectin infusion in dampening inflammation and in reconstruction of damaged periodontal tissues in vivo. Combining our experience and the expert assistance from Drs. Salomon Amar at Boston University and Gerard Karsenty at Columbia University, the completion of this novel project will definitely provide an advanced bioengineering-based tool to allow precise and predictable control of inflammatory resolution and reconstruction of damaged periodontal tissues. PUBLIC HEALTH RELEVANCE: Prevalent type II diabetes mellitus and obesity predispose patients to refractory periodontitis leading to tooth loss, and the inflammatory factors released from periodontal foci enhance and accelerate the formers. Adiponectin, a fat tissue derived hormone, will prove to be a potent bona fide therapeutic molecule, for the first time, to break the "vicious cycle" and to provide a novel, unique and efficient remedy for treating this devastating and sometimes rampant disease.

描述（由申请人提供）：牙周炎在糖尿病患者中的患病率是非糖尿病患者的两倍。糖尿病牙周病更加严重和难治，因为 T2DM 和肥胖会引发过量炎症因子的释放，例如 TNF-1 和 IL-6，进而刺激破骨细胞吸收支撑牙齿的牙槽骨。脂联素是一种脂肪细胞衍生的激素，正在成为一种有效的分子，具有多种生物功能，包括调节胰岛素敏感性、抑制炎症和改善糖尿病症状。它还促进成骨细胞分化和骨形成。我们最近的研究表明脂联素抑制破骨细胞分化并增加破骨细胞凋亡。我们的长期目标是确定并表征一种理想的内源性介质，作为治疗广泛流行的 T2DM 相关牙周炎的有效治疗药物。本申请的目的是研究脂联素在T2DM相关牙周炎发病机制中的作用机制，并通过体内补充脂联素来特异性重建炎症损伤的牙周组织。待检验的中心假设是，脂联素水平的降低，以及随之而来的其对破骨细胞和促炎因子的抑制作用的消除，导致了 T2DM 和 T2DM 相关牙周炎的发病机制。此外，全身脂联素输注可促进受损牙周组织的重建。目标1：首次使用动物模型确定抗炎因子在牙周发病机制中的作用，包括抑制直接吸收牙槽骨的破骨细胞的分化。目标 2：确定全身脂联素输注在抑制炎症和重建体内受损牙周组织方面的治疗效果。结合我们的经验和博士的专家帮助。波士顿大学的 Salomon Amar 和哥伦比亚大学的 Gerard Karsenty 认为，这个新项目的完成肯定会提供一种先进的基于生物工程的工具，以实现精确和可预测的控制炎症消退和受损牙周组织的重建。公众健康相关性：流行的二型糖尿病和肥胖使患者容易患难治性牙周炎，导致牙齿脱落，而牙周病灶释放的炎症因子会增强和加速前者的发生。脂联素是一种脂肪组织衍生的激素，将首次被证明是一种有效的真正治疗分子，可以打破“恶性循环”，并为治疗这种毁灭性且有时猖獗的疾病提供新颖、独特和有效的疗法。