Paneth cells-derived IL-17A and liver ischemia reperfusion injury

潘氏细胞源性IL-17A与肝脏缺血再灌注损伤

基本信息

批准号：
10415225
负责人：
Adam David Griesemer
金额：
$ 68.71万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415225
关键词：
Acute Renal Failure with Renal Papillary Necrosis Ankylosing spondylitis Apoptosis Attenuated Autoimmune Diseases Cell Degranulation Cell model Clinical Coupled Data Excision Extrahepatic Functional disorder Genetic Goals Hepatic Human In Vitro Incidence Inflammation Inflammatory Injury Injury to Kidney Interleukin-17 Intestines Ischemia Kidney Liver Macaca fascicularis Mediating Modeling Monkeys Mus Necrosis Operative Surgical Procedures Organ Paneth Cells Patients Portal vein structure Postoperative Period Procedures Psoriasis Psoriatic Arthritis Reconstructive Surgical Procedures Reperfusion Injury Reperfusion Therapy Sepsis Small Intestines Source Systemic Inflammatory Response Syndrome Testing base clinical translation clinically significant cytokine gut inflammation in vivo intestinal barrier intestinal crypt intestinal injury intrahepatic ischemic injury liver injury liver ischemia liver transplantation lung injury multiorgan injury neutralizing antibody nonhuman primate novel organ injury prevent reconstruction targeted treatment therapy development translational approach

项目摘要

Liver ischemia and reperfusion (IR) injury is a clinically significant problem during and after liver transplantation, hepatic resection and portal vein reconstruction surgery. Unfortunately, there is no therapy to prevent or treat hepatic IR injury. Furthermore, it is becoming increasingly clear that liver IR injury frequently results in significant extra-hepatic remote organ injury including kidney, intestinal and lung injury as well as a systemic inflammatory response syndrome and sepsis. In particular, the incidence of acute kidney injury after liver resection is extremely high and approaches ~50-80% after major hepatic resection or liver transplantation. Our previous studies implicate small intestinal crypt Paneth cells as the initiator of extra-hepatic remote organ injury after liver IR in mice. Furthermore, small intestinal Paneth cells are the predominant source of pro- inflammatory cytokine IL-17A required for generating hepatic and extra-hepatic injury in mice. However, for clinical translation of these studies leading to therapy, it is critical that we determine whether Paneth cell dysregulation and degranulation as well as Paneth cell release of IL-17A also occur after hepatic IR in human and nonhuman primate liver IR injury models. In this proposal, we will elucidate whether small intestinal Paneth cells dysregulate and release pro-inflammatory IL-17A after human and nonhuman primate liver IR injury and whether IL-17A neutralization attenuates liver injury as well as extra-hepatic organ injury after nonhuman primate IR. Exciting preliminary data suggest that cynomolgus monkey liver IR causes profound Paneth cell degranulation and Paneth cell IL-17A induction coupled with rapid kidney and small intestine injury. Furthermore, our preliminary data suggest that cynomolgus monkeys treated with IL-17A neutralizing antibody had markedly less hepatic IR injury as well as reduced post-operative AKI. Preliminary data also suggest that human small intestine Paneth cells degranulate after ischemic injury. Based on these preliminary findings, we hypothesize that hepatic IR injury leads to intestinal Paneth cell dysregulation/degranulation and Paneth cell- derived IL-17A induction leading to intestinal inflammation and apoptosis, subsequent exacerbation of hepatic injury and induction of acute kidney injury. We also hypothesize that IL-17A neutralization will attenuate hepatic, intestinal and kidney injury after liver IR in nonhuman primates. We will utilize both in vivo (highly translational cynomolgus monkey liver IR and human liver transplant studies) and in vitro (freshly isolated cynomolgus monkey and human Paneth cells) models to further elucidate the mechanisms and potential therapy for intestinal and renal injury after hepatic IR by testing the following three specific aims. Aim #1: To demonstrate remote organ injury and Paneth cell degranulation after liver IR injury. Aim #2: To demonstrate Paneth cell-mediated IL-17A release after liver IR injury. Aim #3: To develop therapies to reduce non-human primate liver IR injury induced hepatic and extra-hepatic organ injury.

肝脏缺血再灌注（IR）损伤是肝脏移植期间和移植后的一个具有临床意义的问题。移植、肝切除和门静脉重建手术。不幸的是，没有治疗方法预防或治疗肝IR损伤。此外，越来越清楚的是，肝脏 IR 损伤经常发生导致严重的肝外远端器官损伤，包括肾、肠和肺损伤以及全身炎症反应综合征和败血症。尤其是术后急性肾损伤的发生率肝切除率极高，在大面积肝切除或肝移植后接近 50-80%。我们之前的研究表明小肠隐窝潘氏细胞是肝外远端器官的启动子小鼠肝脏IR后损伤。此外，小肠潘氏细胞是pro-的主要来源。在小鼠中产生肝脏和肝外损伤所需的炎症细胞因子 IL-17A。然而，对于这些研究导致治疗的临床转化，至关重要的是我们确定潘氏细胞是否人类肝脏 IR 后也会发生失调和脱颗粒以及潘氏细胞释放 IL-17A 和非人灵长类动物肝脏IR损伤模型。在本提案中，我们将阐明小肠是否人和非人灵长类动物肝脏 IR 后潘氏细胞失调并释放促炎性 IL-17A 损伤以及 IL-17A 中和是否减轻肝损伤以及肝外器官损伤非人类灵长类动物 IR。令人兴奋的初步数据表明食蟹猴肝脏 IR 会导致严重的潘氏细胞脱颗粒和潘氏细胞 IL-17A 诱导以及快速的肾脏和小肠损伤。此外，我们的初步数据表明，用 IL-17A 中和抗体处理的食蟹猴肝 IR 损伤明显减少，术后 AKI 也减少。初步数据还表明人小肠潘氏细胞在缺血性损伤后脱粒。根据这些初步调查结果，我们假设肝 IR 损伤导致肠道潘氏细胞失调/脱粒和潘氏细胞- 衍生的 IL-17A 诱导导致肠道炎症和细胞凋亡，随后加剧肝损伤损伤和诱发急性肾损伤。我们还假设 IL-17A 中和作用会减弱非人灵长类动物肝脏 IR 后的肝、肠和肾损伤。我们将在体内利用两者（高度转化食蟹猴肝脏 IR 和人类肝脏移植研究）和体外（新鲜分离食蟹猴和人类潘氏细胞）模型进一步阐明其机制和潜力通过测试以下三个具体目标来治疗肝 IR 后的肠道和肾脏损伤。目标#1：证明肝脏 IR 损伤后远端器官损伤和潘氏细胞脱颗粒。目标#2：证明肝脏 IR 损伤后潘氏细胞介导的 IL-17A 释放。目标#3：开发治疗方法以减少非人灵长类动物肝脏 IR 引起的肝脏和肝外损伤器官损伤。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Papper Event 2021: The COVID-19 Pandemic: Lessons Learned and the Way Forward.

2021 年纸质活动：COVID-19 大流行：经验教训和前进方向。

DOI：
发表时间：
2022-01-01
期刊：
影响因子：
3.7
作者：
Sun, Lena S;Brambrink, Ansgar;Emala, Charles W;Hua, May;Lee, H Thomas;Levy, Richard J;Smiley, Richard M;Whittington, Robert A;Narula, Jacquelin H
通讯作者：
Narula, Jacquelin H