Role of NLRP3 signals in ischemia/reperfusion-induced organ injury

NLRP3信号在缺血/再灌注引起的器官损伤中的作用

基本信息

批准号：
10494248
负责人：
Dianne B Mckay
金额：
$ 39.05万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2021-09-24 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10494248
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Blood Vessels Blood flow Bone Marrow Transplantation Cell Death Cell Death Signaling Process Cells Cellular Stress Clinical Complex Data Development Disease Elements Engineering Epithelial Epithelial Cells Evaluation Functional disorder Goals Health Host Defense Human Hypoxia IL18 gene Immune Immunologic Receptors Impairment Inflammasome Inflammatory Infiltrate Injury Injury to Kidney Innate Immune System Ischemia Kidney Knowledge Laboratories Lead Learning Mediating Modeling Mus Operative Surgical Procedures Organ Outcome Pathway interactions Patients Pattern recognition receptor Play Prevention therapy Preventive Production Proteins Proximal Kidney Tubules Renal tubule structure Reperfusion Injury Reperfusion Therapy Research Research Design Research Methodology Role Sepsis Shock Signal Pathway Signal Transduction Testing Therapeutic Tissues Transplantation Tubular formation antimicrobial base cell type clinical development clinically relevant cytokine defense response design detector experimental study gain of function mutation genetic approach improved in vivo in vivo Model infection risk injured loss of function medication safety meetings novel therapeutic intervention organ injury pre-clinical preservation prevent renal hypoxia renal ischemia response response to injury small molecule inhibitor targeted treatment therapeutic target tissue injury

项目摘要

Project Summary: This proposal evaluates how intracellular signaling pathways generated by the cytoplasmic innate immune receptor NLRP3 are regulated in renal tubular epithelial cells. Renal tubule epithelial cells play a central role in ischemic kidney injury, and our lab and others have shown that global NLRP3 blockade can prevent experimental renal ischemia/reperfusion injury. NLRP3 signaling classically results in cell death (pyroptosis), however alternative NLRP3 signaling pathways have recently been identified that lead to secretion of IL1b/IL18 without cell death. Thus, selectively targeting NLRP3-mediated cell death signaling might prevent renal tubule injury while still preserving the host’s ability to secrete IL1b/IL18 and mount needed host defense responses (e.g., antimicrobial responses). The project is highly significant for the development of targeted therapeutics for ischemic kidney injury, which occurs frequently in hospitalized patients and in all organs procured for transplantation. Broad/long-term objectives: The long-term goals of the proposed research are to define how NLRP3 contributes to injurious tissue responses in the kidney and how its signaling can be effectively and selectively targeted. Specific Aims: The specific objective of this proposal is to test the hypothesis that the cytoplasmic pattern recognition receptor NLRP3 can be specifically targeted in renal tubular epithelial cells to selectively block NLRP3-mediated renal tubule cell death, while preserving IL1b/IL18 responses. Aim 1 defines the mechanisms that drive NLRP3 signaling pathways in proximal renal tubule cells. Aim 2 determines how NLRP3 signaling can be selectively targeted in the proximal renal tubule cells. Aim 3 determines how NLRP3 signaling, and its selective blockade, influences renal tubular injury/IL1b/IL18 secretion in vivo, when NLRP3 expression is isolated to the renal tubule epithelium. Research Design and Methods for Achieving the Stated Goals: Aim 1 compares and contrasts activation of NLRP3 in human and murine proximal renal tubular cells and will determine how NLRP3 activation contributes to pyroptosis and/or production of IL1b/IL18. Aim 2 will determine how specific NLRP3 activation pathways can be targeted in the two species to prevent cell death and preserve cytokine secretion. Aim 3 will focus on understanding how NLRP3 restricted to the renal tubule epithelium in vivo can be targeted to prevent renal tubular injury without impairing IL1b/IL18. In the third aim, two different models of NLRP3 expression will be used; one where the renal tubules express a conditional loss-of-function of NLRP3 and another where there is a hyper-activatable form of NLRP3. The studies here will determine whether canonical NLRP3-mediated cell death signaling can be uncoupled from noncanonical signaling to prevent cell death while preserving secretion of IL1b/IL18. Health Relatedness of Project: If the aims of this proposal are met, we will learn how activation of NLRP3 (deemed a central cellular stress detector) can be regulated to target a common disease, renal ischemia/reperfusion injury. This knowledge is crucial for the development of rational targeted therapies for prevention or amelioration of renal ischemia/reperfusion injury in clinical situations where hypoxia is anticipated.

项目摘要：该提案评估细胞内信号通路如何由胞质先天性产生免疫接收器NLRP3在肾小管上皮细胞中受调节。肾小管上皮细胞在缺血性肾脏损伤，我们的实验室和其他实验室表明，全局NLRP3封锁可以防止实验性肾脏缺血/再灌注损伤。 NLRP3信号传导经典导致细胞死亡（Pyroptosis），但是替代性NLRP3 最近已经确定了信号通路，导致无细胞死亡的IL1B/IL18分泌。那，有选择地靶向NLRP3介导的细胞死亡信号传导可能会防止肾管受伤，同时仍保留宿主的能力分泌IL1B/IL18和MOUNT需要宿主防御反应（例如抗菌反应）。该项目高度对于缺血性肾脏损伤的靶向疗法的发展很重要，该治疗经常在住院治疗患者和所有有器官进行移植。广泛/长期目标：拟议研究的长期目标是定义NLRP3如何贡献肾脏中的有害组织反应以及其信号传导如何有效，有选择地靶向。具体目的：该提案的具体目标是检验细胞质模式识别的假设接收器NLRP3可以在肾小管上皮细胞中特异性靶向，以选择性地阻断NLRP3介导的肾脏小管细胞死亡，同时保留IL1B/IL18响应。 AIM 1定义了驱动NLRP3信号传导的机制近端肾小管细胞中的途径。 AIM 2确定如何选择NLRP3信号在近端肾小管细胞。 AIM 3确定NLRP3信号及其选择性阻滞如何影响肾脏当NLRP3表达分离为肾小管上皮时，肾小管损伤/IL1B/IL18体内分泌。实现既定目标的研究设计和方法：AIM 1比较和对比NLRP3的激活在人和鼠近端肾结通细胞中，将确定NLRP3激活如何有助于凋亡和/或IL1B/IL18的生产。 AIM 2将确定如何将特定的NLRP3激活途径靶向这两个物种可防止细胞死亡并保留细胞因子分泌。 AIM 3将专注于了解NLRP3 限于体内肾小管上皮的靶向靶向，以防止肾小管损伤而不会损害IL1B/IL18。在第三个目标中，将使用两种不同的NLRP3表达模型。肾小管表达有条件的一个 NLRP3的功能丧失，另一个具有可激活形式的NLRP3。这里的研究将确定规范NLRP3介导的细胞死亡信号传导是否可以与非规范信号偶联以防止细胞在保留IL1B/IL18的分泌的同时死亡。项目的健康相关性：如果满足该提案的目的，我们将学习如何激活NLRP3（被认为是可以调节中央细胞应力探测器）以靶向常见疾病，肾脏缺血/再灌注损伤。这知识对于开发有理靶向疗法以预防或改善肾脏至关重要在预期缺氧的临床情况下，缺血/再灌注损伤。