Checkpoints of Host Response to Cellular Injuries

宿主对细胞损伤反应的检查点

• 批准号: 7663423
• 负责人: Yang Liu
• 金额: $ 38.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663423
• 关键词: Adult; Antigens; Autoimmune Diseases; Autoimmune Process; Cues; Cytoplasmic Tail; Defect; Development; Funding; HMGB1 gene; ITIM; Immune; Immune response; Immunity; Infection; Inflammation; Inflammatory Response; Injury; Lead; Ligands; Link; Malignant Neoplasms; Mediating; Molecular; Mus; Mutation; NR0B2 gene; Outcome; PTPN11 gene; Pathway interactions; Pattern; Pattern Recognition; Regulation; Role; Signal Transduction; T-Lymphocyte; Testing; Tissues; Toll-like receptors; Transducers; autoreactive T cell; base; cell injury; neonate; novel; pathogen; prevent; public health relevance; receptor; research study; response; sialic acid binding Ig-like lectin; signature molecule

DESCRIPTION (provided by applicant): The last two decades mark a conceptual revolution in immune recognition, switching from one based on engagement of clonal receptor to one that integrates pattern recognition with clonal recognition. The pathogen-associated molecular patterns (PAMP) interacts with several evolutionally conserved pathways, such as Toll-like receptors (TLR) or NOD-like receptors (NLR) to initiate adaptive immune response, although it is now clear that the function of this pattern recognition goes well beyond innate immune protection and initiation of adaptive immunity. In addition to foreign pathogens, the host is also able to respond to injuries through inflammation. Interestingly, one of the signature molecules released during cellular injury, HMGB1, also interacts with TLR. However, this response must be kept under control in order to avoid excessive autoimmune damage following tissue injuries. How the engagement of the same receptor by PAMP would lead to different outcomes than elicited by molecules released during cellular injury remains largely unknown. In the last funding period, we discovered that CD24 on APC negatively regulates T-cell responses to homeostatic cue. In search for molecular mechanisms by which CD24 negatively regulate APC function, we identified two novel CD24 ligands, HMGB1 and SIglec G/10. Based on these discoveries, we hypothesize that CD24 may serve as an important negative regulator for the host response to cellular injury and a molecular mechanism for the negative regulation. This hypothesis will be tested in three sets of experiments. 1). What is the role for CD24-HMGB1 interaction in limiting inflammation, homeostatic proliferation and potential priming of T cells by contents of cellular injuries? We will first study the response of WT and CD24-deficient neonates for their inflammatory response and homeostatic proliferation to HMGB1 stimulation. This will be extended into adult immune competent mice to determine whether CD24 prevent priming of autoreactive T cells specific for antigens released in the context of cellular injury. 2). What is the role for SIglecG/10 in the enhanced homeostatic proliferation? Our preliminary studies indicated that CD24 physically interacts with SIglec 10/G. We will examine the role for SIglecG/10 in APC and T cells in their responses to HMGB1 and determine whether the effect of target mutation with SIglecG and CD24 are interchangeable or synergistic in regulating inflammatory response. 3). What is the molecular mechanism by which CD24 down-regulates inflammatory response initiated by HMGB1? Since SIglecG/10 has ITIM motifs in the cytoplasmic domain that was known to be associated with SHP1 and SHP2, we will test a hypothesis that SIglecG/10 is the signal transducer for CD24-mediated negative regulation. Our proposed studies may reveal a novel pathway for the regulation of host response to cellular injury. Since CD24 defects block the development of autoimmune diseases, our study provides a molecular basis linking inflammation to immunity to cancer or infection without provoking autoimmune diseases. Public Health Relevance: Our proposed studies may reveal a novel pathway for the regulation of host response to cellular injury. Since CD24 defects block the development of autoimmune diseases, our study provides a molecular basis linking inflammation to immunity to cancer or infection without provoking autoimmune diseases.

描述（由申请人提供）：最近二十年标志着免疫识别中的概念革命，从基于克隆受体的参与转变为将模式识别与克隆识别整合在一起的概念。病原体相关的分子模式（PAMP）与几种进化保守的途径相互作用，例如收费类受体（TLR）或类似NOD样受体（NLR）来启动适应性免疫反应，尽管现在很明显，这种模式识别的功能远远超出了天生的免疫保护和自适应免疫的启动。除外国病原体外，宿主还能够通过炎症应对伤害。有趣的是，在细胞损伤期间释放的一个特征性分子HMGB1也与TLR相互作用。但是，必须控制此反应，以避免组织损伤后过度自身免疫性损害。与在细胞损伤期间释放的分子引起的分子所引起的相同受体的接合如何导致不同的结果。在最后一个资金期间，我们发现APC的CD24负调节T细胞对稳态提示的反应。在寻找CD24负调节APC功能的分子机制时，我们确定了两个新型的CD24配体HMGB1和Siglec G/10。基于这些发现，我们假设CD24可以作为宿主对细胞损伤反应的重要负调节剂和负调控的分子机制。该假设将在三组实验中进行检验。 1）。 CD24-HMGB1相互作用在限制炎症，稳态增殖和通过细胞损伤的含量对T细胞的潜在启动的作用是什么？我们将首先研究WT和CD24缺陷新生儿对HMGB1刺激的炎症反应和稳态增殖的反应。这将扩展到成年免疫胜任的小鼠中，以确定CD24是否可以防止在细胞损伤中释放的抗原特异性的自动反应性T细胞。 2）。 Siglecg/10在增强的稳态增殖中的作用是什么？我们的初步研究表明，CD24与SIGLEC 10/g物理相互作用。我们将检查SigleCG/10在APC和T细胞对HMGB1的响应中的作用，并确定SigleCG和CD24靶突变在调节炎症反应中是否可以互换或协同作用。 3）。 CD24降低HMGB1引发的炎症反应的分子机制是什么？由于SigleCG/10在胞质结构域中具有ITIM基序，已知与SHP1和SHP2相关，因此我们将检验一个假设，即SigleCG/10是CD24介导的负调控的信号传感器。我们提出的研究可能揭示了调节宿主对细胞损伤反应的新途径。由于CD24缺陷阻止了自身免疫性疾病的发展，因此我们的研究提供了分子基础，将炎症与对癌症或感染的免疫联系起来，而不会引起自身免疫性疾病。公共卫生相关性：我们提出的研究可能揭示了调节宿主对细胞损伤反应的新途径。由于CD24缺陷阻止了自身免疫性疾病的发展，因此我们的研究提供了分子基础，将炎症与对癌症或感染的免疫联系起来，而不会引起自身免疫性疾病。