Therapeutic Strategies for Treating Type 2 Diabetes Mellitus -Associated Periodon

描述（由申请人提供）：牙周炎在糖尿病患者中的发病率是非糖尿病患者的两倍。糖尿病性牙周病更为严重和难愈，因为T2DM和肥胖会引发过量炎症因子的释放，如TNF-1和IL-6，这反过来刺激破骨细胞重新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，具有调节胰岛素敏感性、抑制炎症和改善糖尿病症状等多种生物学功能。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，增加破骨细胞凋亡。我们的长期目标是确定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手段。本研究旨在探讨脂联素在t2dm相关牙周炎发病中的作用机制，并通过体内脂联素的补充来特异性地重建炎症损伤的牙周组织。要验证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，有助于T2DM和T2DM相关牙周炎的发病机制。此外，全身输注脂联素可促进受损牙周组织的重建。目的1：首次利用动物模型确定抗炎因子在牙周发病中的作用，包括抑制直接吸收牙槽骨的破骨细胞的分化。目的2：观察全身输注脂联素对体内牙周组织损伤的抑制炎症和重建作用。结合我们的经验和博士的专家协助。波士顿大学的Salomon Amar和哥伦比亚大学的Gerard Karsenty说，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，可以精确和可预测地控制炎症消退和受损牙周组织的重建。

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.