Therapeutic Strategies for Treating Type 2 Diabetes Mellitus -Associated Periodon

描述(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。糖尿病牙周疾病更严重和更难治，因为T2 DM和肥胖会触发过量炎症因子的释放，如TNF-1和IL-6，继而刺激破骨细胞吸收支持牙齿的牙槽骨。脂联素是一种脂肪细胞来源的激素，是一种具有多种生物学功能的有效分子，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的分化，增加破骨细胞的凋亡。我们的长期目标是确定和表征一种理想的内源性介质，作为治疗广泛流行的T2 DM相关牙周炎的有效治疗药物。本研究的目的是探讨脂联素在T2 DM相关牙周炎发病机制中的作用，并通过体内补充脂联素的方法对炎症损伤的牙周组织进行特异性修复。需要检验的中心假设是，脂联素水平的降低，以及随之而来的对破骨细胞和促炎因子的抑制作用的消除，导致了T2 DM和T2 DM相关牙周炎的发病。此外，全身注射脂联素可促进受损牙周组织的重建。目的：首次用动物模型研究抗炎因子在牙周病变中的作用，包括抑制直接吸收牙槽骨的破骨细胞的分化。目的：探讨系统注射脂联素在体内抑制炎症反应和修复受损牙周组织中的作用。结合我们的经验以及波士顿大学的所罗门·阿马尔博士和哥伦比亚大学的杰拉德·卡森蒂博士的专家协助，这一新颖项目的完成肯定会提供一种先进的基于生物工程的工具，允许精确和可预测地控制炎症消退和受损牙周组织的重建。 公共卫生相关性：流行的II型糖尿病和肥胖使患者易患顽固性牙周炎，导致牙齿脱落，牙周病灶释放的炎性因子增强和加速了前者。脂联素是一种脂肪组织衍生的激素，它将首次被证明是一种有效的真正的治疗分子，以打破“恶性循环”，并为治疗这种毁灭性的、有时甚至是猖獗的疾病提供一种新颖、独特和有效的药物。

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.