Hyaluronan as an innate ligand that induces inflammation after transplantation

透明质酸作为先天配体，在移植后诱导炎症

• 批准号: 8516457
• 负责人: Daniel Robert Goldstein
• 金额: $ 19.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516457
• 关键词: Acute; Adaptor Signaling Protein; Allograft Tolerance; Allografting; Animal Model; Binding; Biological Models; Cardiac; Cells; Clinical Research; Complement; Delayed Hypersensitivity; Exhibits; Experimental Models; Extracellular Matrix; Future; Generations; Genetic; Graft Rejection; Heart; Hyaluronan; Immune; Immune response; Immune system; Impairment; Inflammation; Inflammatory; Injury; Interleukin-6; Ligands; Mediating; Minor; Modeling; Molecular; Mus; Mutant Strains Mice; Myocardium; Nature; Organ; Organ Transplantation; Pathway interactions; Peptides; Play; Production; Property; Reagent; Resistance; Resources; Role; Signal Transduction; Site; Skin; Skin Transplantation; Skin graft; Sum; System; TNF gene; Tissues; Toll-like receptors; Transgenic Organisms; Transplantation; Transplantation Tolerance; Work; Wound Healing; allograft rejection; cytokine; heart allograft; interest; mouse model; novel; overexpression; prevent; research study; skin allograft; tool

DESCRIPTION (provided by applicant): Components of the innate immune system can contribute to impairment of long term allograft tolerance. However, the molecular activators that trigger the innate immune system to initiate allograft rejection are elusive. Our prior work demonstrates that signaling via MyD88 an adaptor protein downstream of most Toll like receptors on innate immune cells, prevents transplant tolerance. In addition, we have preliminary evidence to suggest that hyaluranan (HA) is an innate ligand that activates the MyD88 inflammatory pathway to initiate allograft rejection and transplant tolerance resistance. We hypothesize that differential HA expression levels in various tissues may explain why some organs, such as the skin, exhibit impaired transplant tolerance, while other tissues, e.g. cardiac allografts, are susceptible to tolerance induction. Deciphering such differences could inform on the generation of novel therapies to inhibit the innate immune response at the site of injury (i.e., within the allograft). In Aim 1 of this proposal, we will employ pharmacological approaches to block HA activity in experimental models of acute transplant rejection and transplantation tolerance for which MyD88 signaling is critical for graft rejection. In Aim 2, we will generate mice in which HA is inducibly deleted within skin allografts. This mouse model will be a useful resource for future experiments to determine if HA mediates MyD88 dependent rejection of skin allografts. We will complement this approach by generating mice in which HA is over-expressed within cardiac tissue. This will allow us to examine whether HA over-expression is sufficient to impair transplant tolerance of cardiac allografts. Hence, this proposal will generate novel reagents to examine the role of HA in acute graft rejection and transplant tolerance induction. Moreover, these resources would also impact other models of inflammation for which HA may play a major role.

描述（由申请人提供）：先天免疫系统的组成部分可以导致长期同种异体耐受性的损害。但是，触发先天免疫系统引发同种异体移植排斥的分子激活剂难以捉摸。我们先前的工作表明，通过MyD88信号传导大多数Toll（如先天免疫细胞）的受体下游的衔接蛋白可防止移植耐受性。此外，我们有初步证据表明，透明质酸（HA）是一种先天配体，可激活MyD88炎症途径以启动同种异体移植排斥和移植耐受性。我们假设各种组织中的差异HA表达水平可以解释为什么某些器官（例如皮肤）表现出受损的移植耐受性，而其他组织则表现出一些器官，例如其他组织，例如心脏同种异体移植物易受耐受性诱导。解密这种差异可以告知新的疗法的产生，以抑制损伤部位（即同种异体移植物）的先天免疫反应。在该提案的目标1中，我们将采用药理学方法来阻止HA活性，这在急性移植排斥和移植耐受性的实验模型中，MyD88信号对于移植物的排斥至关重要。在AIM 2中，我们将生成小鼠，其中HA在皮肤同种异体移植物中被诱导。该小鼠模型将是将来实验的有用资源，以确定HA是否介导了MyD88依赖的皮肤同种异体移植物。我们将通过产生在心脏组织中HA过表达的小鼠来补充这种方法。这将使我们能够检查HA过表达是否足以损害心脏同种异体移植的移植耐受性。因此，该建议将产生新的试剂，以检查HA在急性移植排斥和移植耐受诱导中的作用。此外，这些资源还将影响HA可能起主要作用的其他炎症模型。