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（由适用提供）：由器官检索，冷保存和手术期间温暖的缺血时期，缺血 - 灌注损伤（IRI）通常会导致原发性谷物无功能，可能会导致晚期慢性抑制，并有助于可用于移植的供体器官的短缺。目前，尚无特定的治疗方法来防止移植受体中的IRI。此外，IR诱导的组织损伤的机制以及与临床相关的先天免疫调查如何有助于谷物排斥，这是临床肝移植中尚未理解的最挑战的问题之一。我们已经确定了固有的PACAP神经肽在保持肝的“温暖” IRI的非移植模型中维持肝稳态的作用。我们已经表明，PACAP神经肽治疗通过以营营依赖性方式降低巨噬细胞功能来改善肝脏IRI。我们从正在进行的临床研究中的试点数据表明，与患有严重IR损伤的患者相比，PACAP及其接收器优选在人类伊利特肝移植中诱导。在这里，我们建议在延长的肝冷冷缺血的临床相关小鼠模型中分析不同的PACAP信号通路的功能，然后是原位肝移植（OLT）。假设：PACAP介导的巨噬细胞（先天免疫组织组）的PACAP介导的CAMP-PKA信号传导 - 肝细胞（防御臂）界面调节促炎（致病性）和细胞保护作用（稳态）功能，可在OLT中受IRI受IRI的OLT。目标1：定义PACAP神经肽在肝脏IRI中先天免疫组织化学功能中的作用。假设：PACAP抑制TLR4巨噬细胞激活，并促进IR胁迫OLT中的免疫稳态。 AIM 2：评估PACAP神经肽在肝脏IRI中肝脏保护中的作用。假设：PACAP增强了paranchyma细胞自噬并促进肝细胞存活。通过在IR压力OLT的环境中确定一种新型的PACAP介导的神经调节，该提议在全新的先天免疫学和paranchyma cytoprototection的全新背景下提出了肝免疫调节的进步。基于我们的初步实验数据，在临床观察结果的支持下，该探索性提案的发现可能具有很大的基本和实际后果，因为现在被认为对改善短期和长期移植量的驯化IR触发的先天注射现在被认为是至关重要的。