Wnt-4 inhibits peridontitis by attenuating NF-kB

描述（由申请人提供）：该竞争性更新的长期目标是通过抑制核因子κ B （NF-kB）来开发治疗牙周炎的新疗法。牙周炎是最常见的炎症性疾病，经常破坏牙周组织和牙槽骨，导致牙齿失去支撑。更重要的是，越来越多的证据表明，慢性牙周炎症是心血管疾病、口腔癌、糖尿病和其他全身性疾病的重要危险因素。因此，它代表了一个重大的公众关注的人口老龄化。多种促炎分子，包括肿瘤坏死因子（TNF）、白介素-1 （IL-1）、IL-6、IL-8、细胞间粘附分子-1、环氧化酶-2 （COX-2）、基质金属蛋白酶(MMP)-1和MMP-9，与牙周炎症和骨质流失有关。我们小组和其他人的基础科学发现表明，NF-kB是控制促炎分子表达的主要转录因子。利用基因组学和生物信息学方法，我们发现大多数由牙周病原体诱导的早期反应基因依赖于NF-kB。最近，我们还发现NF-kB的激活介导骨吸收与骨形成的解偶联，为牙周炎修复受损提供了新的解释。因此，从开发牙周炎新疗法的角度来看，靶向NF-kB可能比单一细胞因子更有效。在筛选抑制NF-kB的新分子时，我们意外地发现Wnt-4蛋白在体外和体内抑制牙周炎症并促进修复。基于我们的初步研究，在这种竞争性更新中，我们假设Wnt-4通过减弱NF-kB激活来预防牙周炎症和骨质流失。为了验证我们的假设，提出了三个具体目标。目的1是确定Wnt-4是否通过在体内减弱NF-kB激活来预防牙周炎症和牙槽骨丢失。目的2：探讨重组Wnt-4蛋白是否能在体内通过减弱NF-kB激活来抑制牙周炎的进展并维持牙槽骨的形成。目的3：探讨Wnt-4抑制炎症介质诱导的NF-kB活化的分子机制。该结果将为靶向NF-kB预防和治疗牙周炎提供重要的原理证明，并为涉及IKK/NF-kB抑制剂的临床试验奠定重要基础。

DESCRIPTION (provided by applicant): The long-term objectives of this competing renewal are to develop novel therapeutics for periodontitis by inhibiting nuclear factor-kappa B (NF-kB). Periodontitis is the most common inflammatory disease and often destroys periodontal tissues and alveolar bone, resulting in loss of tooth support. More importantly, growing evidence suggests that chronic periodontal inflammation is an important risk factor for cardiovascular disease, oral cancer, diabetes and other systemic diseases. Thus, it represents a significant public concern in the aging population. Multiple pro-inflammatory molecules, including tumor necrosis factor (TNF), interleulin-1 (IL-1), IL-6, IL-8, intercellular adhesion molecule-1, cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP)-1, and MMP-9, are associated with periodontal inflammation and bone loss. Basic science discoveries from our group and others have demonstrated that NF-kB is a master transcription factor that controls the expression of pro-inflammatory molecules. Using genomic and bioinformatic approaches, we have found that the majority of early-response genes induced by periodontal pathogens are dependent on NF-kB. Recently, we also discovered that the activation of NF-kB mediates the uncoupling of bone formation from bone resorption, providing a novel explanation for the compromised repair in periodontitis. Therefore, from the standpoint of developing novel therapeutics for periodontitis, targeting NF-kB may be more effective than single cytokines. In screening for novel molecules that inhibits NF-kB, unexpectedly, we discovered that Wnt-4 proteins inhibited periodontal inflammation and promoted repair in vitro and in vivo. Based on our preliminary studies, in this competing renewal, we hypothesize that Wnt-4 prevents periodontal inflammation and bone loss by attenuating NF-kB activation. Three specific aims are proposed to test our hypothesis. Aim 1 is to determine whether Wnt-4 prevents periodontal inflammation and alveolar bone loss by attenuating NF-kB activation in vivo. Aim 2 is to explore whether recombinant Wnt-4 proteins can inhibit the progression of periodontitis and maintains alveolar bone formation by attenuating NF-kB activation in vivo. Aim 3 is to explore the molecular mechanisms by which Wnt-4 suppresses NF-kB activation induced by inflammatory mediators. The results should provide an important proof-of-principal in the prevention and treatment of periodontitis by targeting NF-kB, and lay the important foundation for the clinical trials involving the IKK/NF-kB inhibitors. PUBLIC HEALTH RELEVANCE: Periodontitis is the most common inflammatory disease and often destroys alveolar bone and periodontal tissues, resulting in loss of tooth support. It is estimated that over 80% of adults over age 30 have periodontal bone loss and 50% of adults over age 60 have advanced periodontitis with several loose teeth due to severe bone loss. More importantly, growing evidence suggests that chronic periodontal inflammation is an important risk factor for cardiovascular disease, oral cancer, diabetes and other systemic diseases. Thus, it represents a significant public concern in the aging population. In this application, we will tet Wnt-4 proteins can inhibit gum diseases and prevent tissue destruction by attenuating inflammatory responses in vitro and in vivo. The findings from this study will have important implications in developing novel biological strategies for treating gum diseases or other inflammatory diseases.