Paneth cells and acute kidney injury

潘氏细胞与急性肾损伤

• 批准号: 9888364
• 负责人: H. Thomas Lee
• 金额: $ 36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888364
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adenosine A2B Receptor; Adrenergic Receptor; Agonist; Anti-Inflammatory Agents; Attenuated; Cell Degranulation; Cell model; Clinical; Creatinine; Data; Development; Functional disorder; Generations; Genetic; Goals; Hepatic; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-17; Intestines; Kidney; Kupffer Cells; Left; Liver; Mediating; Mediator of activation protein; Morbidity - disease rate; Mus; Norepinephrine; Operative Surgical Procedures; Organ; Paneth Cells; Patients; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Production; Reperfusion Injury; Reperfusion Therapy; Role; Small Intestines; Source; TLR1 gene; TLR9 gene; Testing; Text; Tyrosine 3-Monooxygenase; base; design; effective therapy; in vivo; inflammatory disease of the intestine; intestinal crypt; intestinal injury; liver injury; macrophage; mortality; novel; novel therapeutics; organ injury; prevent; renal ischemia; response; septic; systemic inflammatory response; therapeutic development; therapy development; tissue injury; translational approach; Acute Renal Failure with Renal Papillary Necrosis; Adenosine A2B Receptor; Adrenergic Receptor; Agonist; Anti-Inflammatory Agents; Attenuated; Cell Degranulation; Cell model; Clinical; Creatinine; Data; Development; Functional disorder; Generations; Genetic; Goals; Hepatic; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-17; Intestines; Kidney; Kupffer Cells; Left; Liver; Mediating; Mediator of activation protein; Morbidity - disease rate; Mus; Norepinephrine; Operative Surgical Procedures; Organ; Paneth Cells; Patients; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Production; Reperfusion Injury; Reperfusion Therapy; Role; Small Intestines; Source; TLR1 gene; TLR9 gene; Testing; Text; Tyrosine 3-Monooxygenase; base; design; effective therapy; in vivo; inflammatory disease of the intestine; intestinal crypt; intestinal injury; liver injury; macrophage; mortality; novel; novel therapeutics; organ injury; prevent; renal ischemia; response; septic; systemic inflammatory response; therapeutic development; therapy development; tissue injury; translational approach

Ischemic acute kidney injury (AKI) is a major clinical problem with a very high morbidity and mortality rate. Patients with AKI frequently develop remote organ dysfunction including liver and intestinal injury. These extra-renal organ injuries contribute significantly to the overall mortality from AKI. Indeed, most patients who develop AKI do not die due to AKI but succumb from extra-renal complications. Impeding progress for effective therapy, the mechanisms of remote organ injury after ischemic AKI remain obscure. The goal of this proposal is to determine the mechanisms and develop effective treatment for remote organ injury due to ischemic AKI. Recently, we demonstrated that small intestinal Paneth cells play an important role in hepatic and intestinal dysfunction and systemic inflammation after renal ischemia reperfusion (IR) injury in mice. We also demonstrated that Paneth cell-derived IL-17A plays a critical role in generating intestinal and hepatic injury after ischemic AKI. However, the mechanisms that trigger Paneth cell degranulation and dysregulation after renal IR remain obscure. Our long-term goal is to elucidate these mechanisms enabling the development of therapeutic drugs for AKI-induced extra-renal organ dysfunction. Exciting preliminary data generated for this proposal suggest that Toll-like receptor-9 (TLR9) activation may play a role in kidney IR-induced Paneth cell degranulation and IL-17A induction leading to an intestinal inflammatory response and subsequent liver injury. Furthermore, our preliminary data suggest that Paneth cells produce large quantities of norepinephrine in response to IL-17A that further propagates inflammatory response and tissue injury. Finally, preliminary studies suggest that a selective A2b adenosine receptor (AR) agonist induced anti-inflammatory IL-10 generation in Paneth cells and attenuated intestinal and hepatic injury after renal IR. Furthermore, an A2bAR agonist reduced Paneth cell production of IL-17A and norepinephrine after renal IR. Based on these preliminary findings, we hypothesize that ischemic AKI leads to TLR9-mediated Paneth cell degranulation and IL-17A induction leading to Paneth cell-derived norepinephrine synthesis and intestinal and hepatic injury. We will further elucidate the mechanisms and potential therapy for hepatic and intestinal injury after ischemic AKI by testing the following 3 specific aims. Aim #1: To determine the mechanisms of Paneth cell dysregulation and degranulation after renal IR. Aim #2: To demonstrate that Paneth cells synthesize and release norepinephrine as a major mediator of hepatic and intestinal injury induced by renal IR. Aim #3: To develop therapy to reduce AKI induced hepatic and intestinal injury. In summary, our translational proposal aims to provide a novel understanding of the mechanisms of remote organ injury after ischemic AKI. Our proposal also aims to identify novel therapies to reduce systemic complications from ischemic AKI.

缺血性急性肾脏损伤（AKI）是发病率和死亡率很高的主要临床问题。 AKI患者经常出现远程器官功能障碍，包括肝脏和肠损伤。这些 肾外器官损伤对AKI的总体死亡率产生了重大贡献。确实，大多数患者 发展AKI不会因AKI而死亡，而是因肾上部并发症而屈服。阻碍进步 有效的治疗，缺血性AKI后远程器官损伤的机制仍然晦涩难懂。目标的目标 建议是确定机制并为由于 缺血性aki。最近，我们证明了小肠paneth细胞在肝中起重要作用 小鼠肾脏缺血再灌注（IR）损伤后的肠功能障碍和全身炎症。我们 还证明了泛元细胞衍生的IL-17A在产生肠和肝脏中起着至关重要的作用 缺血性AKI后受伤。但是，触发Paneth细胞脱粒和失调的机制 肾脏IR之后保持晦涩难懂。我们的长期目标是阐明这些机制 AKI诱导的肾上腺外器功能障碍的治疗药物。 该提案生成的令人兴奋的初步数据表明，类似收费的受体-9（TLR9）激活可能 在肾脏IR诱导的Paneth细胞脱粒和IL-17A诱导中发挥作用，导致肠道 炎症反应和随后的肝损伤。此外，我们的初步数据表明Paneth 细胞响应IL-17a而产生大量的去甲肾上腺素，从而进一步传播炎症 反应和组织损伤。最后，初步研究表明选择性A2B腺苷受体（AR） 激动剂在泛细胞中诱导抗炎IL-10产生，并减弱肠损伤 肾脏IR之后。此外，A2bar激动剂减少了IL-17A和去甲肾上腺素的Paneth细胞产生 肾脏IR之后。基于这些初步发现，我们假设缺血性AKI导致TLR9介导 Paneth细胞脱粒和IL-17A诱导，导致Paneth细胞衍生的去甲肾上腺素合成和 肠道和肝损伤。我们将进一步阐明肝的机制和潜在疗法 缺血性AKI后肠道损伤通过测试以下3个特定目标。 目标＃1：确定肾脏IR后Paneth细胞失调和脱粒的机制。 目标＃2：证明泛细胞合成并释放去甲肾上腺素作为主要介体 肾脏IR引起的肝和肠损伤。 目标＃3：开发疗法以减少AKI诱发的肝和肠道损伤。 总而言之，我们的翻译建议旨在提供对远程机制的新了解 缺血性AKI后的器官损伤。我们的建议还旨在确定新的疗法以减少系统性 缺血性AKI的并发症。