The cell biology of Toll-like receptor 9: a mechanism to prevent autoimmunity

Toll样受体9的细胞生物学：预防自身免疫的机制

• 批准号: 8016090
• 负责人: Gregory M Barton
• 金额: $ 32.51万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016090
• 关键词: Address; Animals; Autoimmune Diseases; Autoimmunity; Bacterial Genome; Biochemical; Biology; Cell surface; Cells; Cellular biology; Collaborations; DNA; Detection; Discrimination; Double Stranded DNA Virus; Equilibrium; Goals; Grant; Human; Immune response; Immune system; Infection prevention; Lead; Ligands; Longitudinal Studies; Mus; Nucleic Acids; Pathology; Pathway interactions; Patients; Play; Proteins; Regulation; Research; Research Personnel; Role; Sampling; System; Systemic Lupus Erythematosus; TLR9 gene; Techniques; Testing; Time; Toll-like receptors; Viral Genome; Virus; Work; cost; ds-DNA; human disease; mutant; novel; prevent; public health relevance; receptor; response; trafficking; viral DNA

DESCRIPTION (provided by applicant): A subset of Toll-like receptors (TLRs) recognizes the nucleic acids of viral and bacterial genomes. This recognition strategy can come at a significant cost, as these types of nucleic acid are also present in the host. Most of the time, recognition of self nucleic acid is avoided. In some instances, though, TLRs contribute to a vigorous anti-nucleic acid immune response called systemic lupus erythematosus (SLE). This proposal focuses on defining the mechanisms that prevent recognition of self nucleic acid while still allowing detection of foreign nucleic acid. We are addressing this fundamental issue using TLR9 as a representative example of the group of nucleic acid-specific TLRs. TLR9 recognizes unmethylated CpG motifs in double-stranded DNA and has been shown to play a role in the immune response to a number of double-stranded DNA viruses. TLR9 has also been implicated in the pathology of SLE. An intriguing aspect of TLR9 biology is that it does not traffic to the cell surface, but instead localizes to and recognizes ligand within intracellular compartments. We have evidence that the cell biology of TLR9 is regulated at multiple levels. This research application aims to define the mechanisms that regulate TLR9 localization within the cell. In Aim 1 we will define the region within TLR9 necessary for its intracellular retention. In Aim 2, we will use novel biochemical techniques to characterize the pathways that control TLR9 localization and trafficking. Finally, in Aim 3 we express mutant receptors in mice and test the hypothesis that intracellular localization is necessary to avoid self DNA recognition. Collectively, these Aims will address how the cell biology of TLR9 is regulated and will test the importance of this regulation in maintaining proper self/non-self discrimination by this receptor. PUBLIC HEALTH RELEVANCE: This proposal deals with the balance that must be maintained by the immune system between recognition of infection and prevention of autoimmunity. The work focuses on TLR9, a protein that normally recognizes viral DNA, but can sometimes inappropriately recognize self DNA and cause autoimmune disease. The goal of this research is to understand how TLR9 recognizes viral DNA while avoiding self DNA.

描述（由申请人提供）：Toll 样受体 (TLR) 的一个子集识别病毒和细菌基因组的核酸。这种识别策略可能会付出巨大的代价，因为这些类型的核酸也存在于宿主中。大多数时候，避免识别自身核酸。但在某些情况下，TLR 会引发强烈的抗核酸免疫反应，称为系统性红斑狼疮 (SLE)。该提案的重点是定义阻止自身核酸识别同时仍允许检测外源核酸的机制。我们正在使用 TLR9 作为核酸特异性 TLR 组的代表性示例来解决这一基本问题。 TLR9 识别双链 DNA 中的未甲基化 CpG 基序，并已被证明在针对多种双链 DNA 病毒的免疫反应中发挥作用。 TLR9 也与 SLE 的病理有关。 TLR9 生物学的一个有趣的方面是它不会运输到细胞表面，而是定位并识别细胞内的配体。我们有证据表明 TLR9 的细胞生物学在多个层面上受到调节。该研究应用旨在明确调节 TLR9 在细胞内定位的机制。在目标 1 中，我们将定义 TLR9 内其细胞内保留所必需的区域。在目标 2 中，我们将使用新颖的生化技术来表征控制 TLR9 定位和运输的途径。最后，在目标 3 中，我们在小鼠中表达突变受体并测试细胞内定位对于避免自身 DNA 识别是必要的假设。总的来说，这些目标将解决 TLR9 的细胞生物学如何受到调节，并将测试这种调节在维持该受体适当的自我/非自我区分方面的重要性。 公共卫生相关性：该提案涉及免疫系统在识别感染和预防自身免疫之间必须维持的平衡。这项工作的重点是 TLR9，这是一种通常识别病毒 DNA 的蛋白质，但有时会不适当地识别自身 DNA 并导致自身免疫性疾病。这项研究的目的是了解 TLR9 如何识别病毒 DNA，同时避开自身 DNA。