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

基本信息

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
项目类别：
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

项目摘要

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导致长期同种异体移植物耐受性的损害。然而，触发先天免疫系统引发同种异体移植排斥的分子激活剂却难以捉摸。我们之前的工作表明，通过先天免疫细胞上大多数 Toll 样受体下游的接头蛋白 MyD88 发出信号，可以防止移植耐受。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 炎症通路，从而引发同种异体移植排斥和移植耐受抵抗。我们假设不同组织中HA表达水平的差异可以解释为什么一些器官（例如皮肤）表现出移植耐受性受损，而其他组织（例如皮肤）表现出移植耐受性受损。心脏同种异体移植物对耐受诱导敏感。破译这些差异可以为抑制损伤部位（即同种异体移植物内）的先天免疫反应的新疗法的产生提供信息。在本提案的目标 1 中，我们将采用药理学方法来阻断急性移植排斥和移植耐受实验模型中的 HA 活性，其中 MyD88 信号传导对于移植排斥至关重要。在目标 2 中，我们将生成在同种异体皮肤移植物中诱导删除 HA 的小鼠。该小鼠模型将成为未来实验的有用资源，以确定 HA 是否介导 MyD88 依赖性皮肤同种异体移植排斥。我们将通过培育HA在心脏组织内过度表达的小鼠来补充这种方法。这将使我们能够检查 HA 过度表达是否足以损害同种异体心脏移植物的移植耐受性。因此，该提案将产生新的试剂来检查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 可能发挥重要作用的其他炎症模型。公共健康相关性：实验和临床研究均表明，先天免疫系统会导致器官同种异体移植物的急性排斥和移植耐受性抵抗。然而，我们不知道器官移植后激活先天系统的物质的性质。该提案将通过药理学方法和通过产生具有调节透明质酸表达的新型小鼠来检查假定的先天配体透明质酸是否对急性同种异体移植排斥和移植耐受性至关重要。