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: 8242964
• 负责人: Daniel Robert Goldstein
• 金额: $ 24.91万
• 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/8242964
• 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. PUBLIC HEALTH RELEVANCE: Both experimental and clinical studies have revealed that the innate immune system contributes to acute rejection of organ allografts and transplant tolerance resistance. However, we do not know the nature of the substances that activate the innate system after organ transplantation. This proposal will examine whether a putative innate ligand, hyaluronan, is critical for acute allograft rejection and transplant tolerance resistance through pharmacological approaches and through generation of novel mice with modulated hyaluronan expression.

描述(由申请人提供)：先天免疫系统的组成部分可能会损害长期的同种异体移植耐受性。然而，触发先天免疫系统启动同种异体移植排斥反应的分子激活剂是难以捉摸的。我们之前的工作表明，通过MyD88信号传递信号，防止移植耐受。MyD88是天然免疫细胞上大多数Toll样受体下游的适配器蛋白。此外，我们有初步证据表明，透明质酸(HA)是一种天然配体，它激活MyD88炎症途径，启动同种异体移植排斥反应和移植耐受。我们推测，HA在不同组织中的不同表达水平可能解释了为什么某些器官，如皮肤，表现出移植耐受受损，而其他组织，如心脏移植物，对耐受诱导敏感。破译这些差异可以为新疗法的产生提供信息，以抑制损伤部位(即同种异体移植物内)的先天免疫反应。在本提案的目标1中，我们将在急性移植排斥和移植耐受的实验模型中使用药理学方法来阻断HA的活性，在这些模型中，MyD88信号在移植排斥中起关键作用。在目标2中，我们将产生HA在同种异体皮肤移植中被诱导删除的小鼠。这个小鼠模型将是未来实验的有用资源，以确定HA是否介导了MyD88依赖的同种异体皮肤移植排斥反应。我们将通过培育HA在心脏组织中过度表达的小鼠来补充这一方法。这将使我们能够检查HA的过度表达是否足以损害同种异体心脏移植的耐受性。因此，这一建议将产生新的试剂来研究HA在急性移植物排斥反应和移植耐受诱导中的作用。此外，这些资源还会影响其他炎症模型，而医管局可能在其中扮演重要角色。 公共卫生相关性：实验和临床研究都表明，先天免疫系统有助于器官移植的急性排斥反应和移植耐受。然而，我们不知道器官移植后激活固有系统的物质的性质。这项提议将通过药理学方法和通过产生调节透明质酸表达的新型小鼠来检验假定的天然配体透明质酸是否对急性同种异体移植排斥反应和移植耐受至关重要。