Regulation and Function of TLR9

免疫系统的细胞需要识别特有的病毒和细菌分子，以便识别感染。一些免疫细胞可以检测到病毒和细菌DNA的存在。这些细胞通过制造许多抗病毒或抗细菌分子来做出反应，并激活其他细胞来对抗感染。细菌DNA的作用可以通过某些短的合成DNA片段来模仿。这种合成DNA(称为CpG DNA)的强大活性正被用于治疗癌症和过敏的一些临床试验，以及改善疫苗接种。尽管CpG DNA在临床上的应用进展很快，但关于CpG DNA如何作用于细胞仍有许多基本信息需要了解。DNA为了激活细胞而与之结合的分子称为TLR9。TLR9不在细胞表面，而是在细胞内。在细菌感染中，被称为巨噬细胞的细胞吞噬和消化细菌，并释放细胞内的细菌DNA，在那里它与TLR9结合。在其他情况下，包括CpG DNA用于治疗时，DNA需要被带入细胞。有证据表明，细胞表面有一个受体，它与DNA结合，并将其带入细胞。在这个项目中，我们建议鉴定这种DNA摄取受体。除了使用CpG DNA之外，还有许多其他关于DNA治疗用途的建议。虽然已经知道DNA进入细胞，但这条路线还没有建立起来。虽然CpG DNA可以激活免疫细胞，但其他一些不同的DNA分子可以阻止这种激活。我们将研究这些抑制性DNA分子是否比CpG DNA更有效地与TLR9结合，但不激活细胞。这些抑制分子被建议用于治疗自身免疫性疾病狼疮，这种疾病涉及对DNA的不适当反应，被认为与TLR9有关。为了开发治疗方法，对它们如何起作用的详细知识是必不可少的。

Cells of the immune system need to recognise characteristic viral and bacterial molecules, in order to identify infection. Some immune cells can detect the presence of viral and bacterial DNA. The cells respond by making a number of anti-viral or anti-bacterial molecules, as well as activating other cells to fight the infection. The effect of bacterial DNA can be mimicked by certain short synthetic pieces of DNA. The potent activity of this synthetic DNA (termed CpG DNA ) is being exploited in a number of clinical trials for treatment of cancer and allergy, as well as to improve vaccinations. Despite the rapid advance towards clinical application, there is still much basic information to learn about how CpG DNA acts on cells. The molecule to which DNA binds in order to activate the cells is called TLR9. TLR9 is not on the surface of cells, but within cells. In a bacterial infection, cells called macrophages engulf and digest bacteria and release the bacterial DNA within the cell, where it binds to TLR9. In other cases, including when CpG DNA is used therapeutically, the DNA needs to be taken up into the cell. Evidence shows that there is a receptor on the cell surface which binds DNA, and takes it into the cell. In this project we propose to identify this DNA uptake receptor. Apart from the use of CpG DNA, there are a number of other proposals for the therapeutic use of DNA. Although it is known that DNA enters into cells, the route for this has not been established. Whilst CpG DNA can activate immune cells, some other distinct DNA molecules can prevent the activation. We will examine whether these inhibitory DNA molecules bind more effectively to TLR9 than the CpG DNA, but do not activate the cell. These inhibitory molecules are proposed as a therapy for the autoimmune disease lupus, which involves inappropriate responses to DNA, and is thought to involve TLR9. In order to develop therapies, a detailed knowledge of how they work is essential.