Dendritic Cells and Periodontal Disease

项目摘要 在该奖项的最初资助期，我们提供了确凿的证据，证明树突状细胞在 FOXO1和Akt1在牙周病的发病机制中起重要作用，并且这种作用是通过FOXO1和Akt1调节的。 与我们的预期相反，树突状细胞中的谱系特异性FOXO1缺失显著增加 对牙周炎的易感性，而当树突状细胞中Akt1缺失时，结果正好相反。 DC特异性Akt1缺失可抑制细菌引起的牙周炎，而DC特异性FOXO1缺失可抑制细菌引起的牙周炎 增加了它。这些令人兴奋的结果提供了第一个具体的证据，表明DC在 调节对牙周炎的易感性，并提示通过Akt1和FOXO1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。它们可能会产生一些因素 这可能有利于Tregs的形成，Tregs已被证明可以减少牙周破坏。他们也 可以引导产生具有潜在保护性的抗体反应。或者，DC可以 转分化为破骨细胞，即负责骨吸收的效应细胞。我们将逐一进行检查 FOXO1和Akt1调节DC控制易感性的三种可能机制 牙周炎。我们提出了FOXO1/Akt1调节易感性的三种机制 牙周炎。这些机制是相互兼容的，这三种机制都有可能发挥作用。 实验包括牙周炎和牙周炎的活体实验模型。 在树突状细胞中具有谱系特异性FOXO1或Akt1缺失的小鼠中，以及伴随的体外研究。目标是 目的1是建立树突状细胞中FOXO1调节牙周病的机制 目标2的目标是建立Akt1起相反作用的机制。 三种兼容的机制将被研究，通过改变调节适应性免疫反应 Treg/Th2与Th1/Th17反应，抗体反应的改变，提供保护 牙周破坏，未成熟DC向破骨细胞转分化。

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.