Dendritic Cells and Periodontal Disease

项目摘要 在该奖项的最初资助期间，我们提供了确凿的证据，证明树突状细胞在肿瘤的发生中起着核心作用。 在牙周病的发病机制中的作用，这种功能是通过FOXO 1和Akt 1调节的。 与我们的预期相反，树突状细胞中谱系特异性FOXO 1缺失显著增加， 牙周炎的易感性，而相反的结果发生时，Akt 1在树突状细胞中删除。 DC特异性Akt 1缺失阻断细菌诱导的牙周炎，而DC特异性FOXO 1缺失 这些令人兴奋的结果提供了第一个具体的证据，表明DC发挥了重要作用， 调节牙周炎的易感性，并提出了通过Akt 1和FOXO 1的机制。树突状细胞 具有多种功能，可影响牙周炎和骨质流失。它们可能产生因子 这可能有利于牙周炎的形成，而牙周炎已被证明可以减少牙周病的发生。他们还 可以指导产生具有潜在保护作用的抗体反应。或者，发展中国家可以 转分化为破骨细胞，即负责骨吸收的效应细胞。我们将逐一检查 FOXO 1和Akt 1可能通过三种潜在机制调节DC以控制对 牙周炎我们提出了FOXO 1/Akt 1可以调节易感性的三种机制， 牙周炎这些机制是相互兼容的，所有三个都可能发挥作用。 本实验采用牙龈卟啉单胞菌和具核梭菌诱导牙周炎的体内实验模型 在DC中具有谱系特异性FOXO 1或Akt 1缺失的小鼠中，沿着体外研究。目标 目的1是建立树突状细胞中FOXO 1调节牙周病的机制 目的2的目标是建立Akt 1具有相反作用的机制。 将研究三种相容的机制，通过改变免疫原性来调节适应性免疫应答。 Treg/Th 2相对于Th 1/Th 17应答，抗体应答的改变，其赋予抗 牙周破裂和未成熟DC向破骨细胞的转分化。

Project Summary In the initial funding period of this award we provided conclusive evidence that dendritic cells play a central role in the pathogenesis of periodontal disease and that this function is modulated through FOXO1 and Akt1. Contrary to our expectations, lineage specific FOXO1 deletion in dendritic cells significantly increased susceptibility to periodontitis whereas the opposite result occurred when Akt1 was deleted in dendritic cells. DC-specific Akt1 deletion blocked bacteria-induced periodontitis whereas DC-specific FOXO1 deletion increased it. These exciting results provide the first concrete evidence that DC play an instrumental role in modulating susceptibility to periodontitis and suggest a mechanism through Akt1 and FOXO1. Dendritic cells have multiple functions that can affect periodontal inflammation and bone loss. They may produce factors that may favor the formation of T regs, which have been shown to reduce periodontal breakdown. They also can direct the production of an antibody response that is potentially protective. Alternatively, DCs can transdifferentiate to osteoclasts, effector cells responsible for bone resorption. We will examine each of these three potential mechanisms through which the FOXO1 and Akt1 May regulate DC to control susceptibility to periodontitis. We propose three mechanisms by which FOXO1/Akt1 can modulate susceptibility to periodontitis. These mechanisms are compatible with each other and all three could potentially play a role. The experiments involve an in vivo experimental model of P gingivalis and F nucleatum induced periodontitis in mice with lineage specific FOXO1 or Akt1 deletion in DC along with companion in vitro studies. The goal of Aim 1 is to establish mechanisms through which FOXO1 in dendritic cells modulates periodontal disease susceptibility, while the goal of Aim 2 is to establish mechanisms through which Akt1 has the opposite effect. Three compatible mechanisms will be investigated, modulation of the adaptive immune response by altering Treg/Th2 versus Th1/Th17 responses, alteration of an antibody response that confers protection against periodontal breakdown, and transdifferentiation of immature DC to osteoclasts.