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PACAP Mediated Neural Regulation of Hepatic Inflammation in Orthotopic Liver Transplantation

PACAP 介导原位肝移植中肝脏炎症的神经调节

基本信息

批准号：
9248242
负责人：
Haofeng Ji
金额：
$ 23.1万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9248242
关键词：
Acute Adrenal Glands Amino Acids Animal Model Anterior Hypothalamus Autophagocytosis Biological Process Brain Stem C-terminal CREB1 gene Cells Chemicals Chronic Clinical Clinical Research Communication Complex Complication Cryopreservation Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytoprotection Data Depressed mood Excision FOXO1A gene Family Feedback G-Protein-Coupled Receptors Gastrointestinal tract structure Gene Expression Genetic Transcription Glucagon Graft Rejection Hemorrhagic Shock Hepatic Hepatocyte Homeostasis Hormonal Human Hypothalamic structure Immune Immune signaling Immune system Inflammation Inflammation Mediators Inflammatory Inflammatory Response Innate Immune Response Innate Immune System Interleukin-1 beta Interleukin-6 Ischemia Liver Liver diseases Lung diseases Lymphoid Lymphoid Cell Macrophage Activation Mediating Metabolic Modeling Molecular Monitor Mus NF-kappa B Natural Immunity Nervous system structure Neuropeptides Neurosecretory Systems Operative Surgical Procedures Organ Organ Donor Organ Retrievals Outcome Output PACAP27 PACAP38 Pancreas Pathogenicity Patients Pattern Peripheral Physiological Preoptic Areas Reflex action Reperfusion Injury Reperfusion Therapy Resistance Role Sarcoidosis Secretin Sentinel Signal Pathway Signal Transduction Site Spleen Stress TLR4 gene TNF gene Therapeutic Thymus Gland Tissues Transplant Recipients Transplantation Vagus nerve structure Vasoactive Intestinal Peptide Warm Ischemia animal data arm base beta catenin biological adaptation to stress clinically relevant immune activation immunoregulation improved innate immune function liver inflammation liver ischemia liver transplantation lymph nodes macrophage mouse model neuroregulation novel pathogen pituitary adenylate cyclase activating polypeptide prevent public health relevance receptor relating to nervous system response vasoactive intestinal peptide receptor 1

项目摘要

DESCRIPTION (provided by applicant): Resulting from organ retrieval, cold preservation and a period of warm ischemia during the surgery, ischemia-reperfusion injury (IRI) often leads to primary graft non-function, may predispose to late chronic rejection, and contributes to the shortage of donor organs available for transplantation. At present, there is no specific treatment available to prevent IRI in transplant recipients. Moreover, mechanisms of IR-induced tissue damage, and how clinically-relevant innate immune responses contribute to graft rejection represents one of the most challenging yet understudied problems in clinical liver transplantation. We have identified the role of intrinsic PACAP neuropeptide in maintaining hepatic homeostasis in a non-transplant model of hepatic "warm" IRI. We have shown that treatment with PACAP neuropeptide ameliorated liver IRI by depressing macrophage function in cAMP-PKA dependent manner. Our pilot data from an ongoing clinical study show that PACAP and its receptors are preferentially induced in human IRI-resistant liver transplants, as compared to those suffering from severe IR-damage. Here, we propose to analyze the function of distinct PACAP signaling pathways in a clinically relevant mouse model of prolonged hepatic cold ischemia followed by orthotopic liver transplantation (OLT). Hypothesis: PACAP-mediated cAMP-PKA signaling at the macrophage (innate immune arm) - hepatocyte (defensive arm) interface regulates pro-inflammatory (pathogenic) and cytoprotective (homeostatic) functions in OLTs subjected to IRI. Aim 1: To define the role of PACAP neuropeptide in innate immune function in liver IRI. Hypothesis: PACAP inhibits TLR4 macrophage activation and promotes immune homeostasis in IR-stressed OLTs. Aim 2: To evaluate the role of PACAP neuropeptide in hepatoprotection in liver IRI. Hypothesis: PACAP enhances parenchyma cell autophagy and promotes hepatocyte survival. By identifying a novel PACAP mediated-neural regulation in the milieu of IR-stressed OLTs, this proposal puts forth the advances in hepatic immune modulation in a completely new context of innate immunity and parenchyma cytoprotection. Based on our preliminary experimental data, supported by clinical observations, findings from this exploratory proposal may have far reaching basic and practical ramifications, as taming of IR-triggered innate inflammation at the graft site is now considered critical for improving both short and long-term transplantation outcomes.

描述（申请人提供）：由于手术过程中器官的取出、冷藏和一段时间的热缺血，缺血再灌注损伤（IRI）常常导致移植物原发性无功能，可能导致晚期慢性排斥反应，并导致可供移植的供体器官短缺。目前，没有特定的治疗方法可以预防移植受者的 IRI。此外，IR引起的组织损伤的机制，以及临床相关的先天免疫反应如何导致移植物排斥，是临床肝移植中最具挑战性但尚未得到充分研究的问题之一。我们已经确定了内在 PACAP 神经肽在肝脏“温”IRI 非移植模型中维持肝脏稳态中的作用。我们已经表明，PACAP 神经肽治疗通过以 cAMP-PKA 依赖性方式抑制巨噬细胞功能来改善肝脏 IRI。我们来自一项正在进行的临床研究的初步数据表明，与遭受严重 IR 损伤的患者相比，PACAP 及其受体在人类抗 IRI 肝移植中优先被诱导。在这里，我们建议分析不同 PACAP 信号通路在长期肝冷缺血、随后进行原位肝移植 (OLT) 的临床相关小鼠模型中的功能。假设：PACAP 介导的巨噬细胞（先天免疫臂）-肝细胞（防御臂）界面上的 cAMP-PKA 信号传导可调节遭受 IRI 的 OLT 的促炎（致病）和细胞保护（稳态）功能。目标 1：明确 PACAP 神经肽在肝脏 IRI 的先天免疫功能中的作用。假设：PACAP 抑制 TLR4 巨噬细胞活化并促进 IR 应激的 OLT 中的免疫稳态。目的 2：评估 PACAP 神经肽在肝脏 IRI 中的保肝作用。假设：PACAP 增强实质细胞自噬并促进肝细胞存活。通过在 IR 应激的 OLT 环境中确定一种新型 PACAP 介导的神经调节，该提案在先天免疫和实质细胞保护的全新背景下提出了肝脏免疫调节的进展。根据我们的初步实验数据，并得到临床观察的支持，这一探索性提议的结果可能具有深远的基础和实际影响，因为驯服移植部位由红外线引发的先天炎症现在被认为对于改善短期和长期移植结果至关重要。