Regulation and Function of TLR9

TLR9的调控和功能

• 批准号: nhmrc : 455882
• 负责人: A/Pr Katryn Stacey
• 金额: $ 17.13万
• 依托单位: The University of Queensland
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/regulation-function-tlr9/81048
• 关键词: Regulation; Function; TLR9

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.

免疫系统的细胞需要识别特征性的病毒和细菌分子，以识别感染。一些免疫细胞可以检测到病毒和细菌DNA的存在。这些细胞通过制造一些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）的有效活性正在许多临床试验中用于治疗癌症和过敏，以及改善疫苗接种。尽管临床应用进展迅速，但仍有许多关于CpG DNA如何作用于细胞的基本信息需要了解。与DNA结合以激活细胞的分子称为TLR9。TLR9不是在细胞表面，而是在细胞内。在细菌感染中，称为巨噬细胞的细胞吞噬和消化细菌，并在细胞内释放细菌DNA，在那里它与TLR9结合。在其他情况下，包括当CpG DNA用于治疗时，DNA需要被吸收到细胞中。有证据表明，在细胞表面有一个受体，它结合DNA，并将其带入细胞。在这个项目中，我们建议确定这种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。虽然已知DNA进入细胞，但其途径尚未确定。虽然CpG DNA可以激活免疫细胞，但其他一些不同的DNA分子可以阻止激活。我们将研究这些抑制性DNA分子是否比CpG DNA更有效地结合TLR9，但不激活细胞。这些抑制性分子被提议作为自身免疫性疾病狼疮的治疗方法，其涉及对DNA的不适当反应，并被认为涉及TLR9。为了开发治疗方法，详细了解它们如何工作是必不可少的。