Sphingolipids in Acute Kidney Injury

急性肾损伤中的鞘脂

基本信息

批准号：
8440366
负责人：
Mark Douglas Okusa
金额：
$ 30.53万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2015-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8440366
关键词：
Ablation Acute Renal Failure with Renal Papillary Necrosis Address Adoptive Transfer Adverse effects Agonist Attenuated Autoimmune Diseases Biological Bone Marrow Bone Marrow Cells Breeding Cell Maturation Cell Surface Receptors Cell membrane Cell physiology Cells Characteristics Chimera organism Clinical Clinical Research Clinical Trials Data Dendritic Cells Dendritic cell activation Development Diphtheria Toxin Disease Effector Cell End stage renal failure Endothelial Cells Epithelial Epithelial Cells Event Exposure to Family Foundations Functional disorder Future G-Protein-Coupled Receptors German population Goals Human IL17 gene Immune Immune response Immune system In Vitro Incidence Inflammation Injury Interleukin-12 Ischemia Isomerism Kidney Knockout Mice Knowledge Laboratories Lead Lymphocyte Lymphopenia Mediating Methods Modeling Molecular Mouse Strains Multiple Sclerosis Mus Myeloid Cells NCI Center for Cancer Research Natural Immunity Organ Pathology Pathway interactions Peripheral Pharmaceutical Preparations Phosphoenolpyruvate Carboxylase Physiological Play Prevalence Property Publishing Renal function Reperfusion Injury Reperfusion Therapy Research Research Proposals Role Series Signal Transduction Sphingolipids Sphingosine-1-Phosphate Receptor Tamoxifen Testing Therapeutic Agents Therapeutic Intervention Tissues Toxin Transgenic Mice Vascular Endothelium Wild Type Mouse analog cellular targeting design edg-3 Protein extracellular in vivo killer T cell mortality novel novel therapeutic intervention novel therapeutics prevent promoter protective effect public health relevance receptor recombinase reconstitution renal ischemia response small molecule sphingosine 1-phosphate tool trafficking treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The overall goal of the research proposed is to understand the mechanisms of acute kidney injury (AKI) to enable the design of new therapeutic agents to prevent and treat this devastating disorder. One strategy that has evolved over the last few years involves sphingosine 1-phosphate receptor (S1PR) agonists. These compounds abrogate the pathology associated with ischemia-reperfusion injury (IRI) of the kidney and other organs. Cellular sphingolipids are metabolized rapidly to a series of bioactive intermediates including sphingosine 1-phosphate (S1P) following stimulation of cell membrane receptors or injury to plasma membranes. S1P has diverse cellular signaling responses on immune and nonimmune cells through cell surface receptors. This proposal focuses on the extracellular effects of S1P analogs through S1P1R and S1P3Rs on immune cells as well as cellular mechanisms of kidney inflammation and injury. Our preliminary data suggest that the protective effect of S1P1R agonists is, in part, independent of S1P agonist's canonical effect - inhibition of lymphocyte trafficking resulting in lymphopenia, because S1P1R agonists protected kidneys from IRI in Rag-1 null mice that lack T, B and NKT cells. Thus S1P1Rs on proximal tubule epithelial cells, endothelial cells or myeloid cells (dendritic cells) could serve as important cellular targets in mediating tissue protection. We also found that the absence of bone marrow derived S1P3Rs confers tissue protection. These data and the observation that S1P1Rs and S1P3Rs are the most abundantly expressed S1PRs in kidney undergird the current proposal focusing on the extrinsic cell function of these two receptor subtypes in mediating tissue protection. We hypothesize that: 1) S1P1R activation and S1P3R antagonism mediate tissue protection in epithelial and endothelial cells. 2) Ideal novel compounds in mediating tissue protection have agonist activity at S1P1R and antagonist activity of S1P3R. Three aims are proposed: Aims 1 tests the hypothesis that S1P1R activation on epithelial and endothelial cells mediate proximal tubule tissue protection. Aim 2 tests the hypothesis that S1P1R activation and S1P3R deficiency attenuates dendritic cell activation of the innate immune response to IRI and Aim 3 tests the hypothesis that new compounds that possess agonist activity at S1P1R and antagonist activity at S1P3Rs are ideal characteristics in mediating tissue protection. We will use wild type and genetically modified mice, chimeric mice, immune cell ablation studies using diptheria toxin in susceptible transgenic mouse strains, adoptive transfer studies, and cultured immune cells to address mechanistic questions both in vivo and in vitro. Furthermore our methods will incorporate immunological, cell biological, molecular and physiological tools in executing each aim. Our long-term plan is to better understand the role of an important class of receptors that that will enable the development of new therapeutic interventions with compounds for S1P receptors to block the deleterious consequences of acute kidney injury.

描述（由申请人提供）：所提议研究的总体目标是了解急性肾损伤（AKI）的机制，以便能够设计新的治疗药物来预防和治疗这种破坏性疾病。过去几年发展起来的一种策略涉及 1-磷酸鞘氨醇受体 (S1PR) 激动剂。这些化合物消除了与肾脏和其他器官的缺血再灌注损伤（IRI）相关的病理学。在刺激细胞膜受体或损伤质膜后，细胞鞘脂迅速代谢为一系列生物活性中间体，包括 1-磷酸鞘氨醇 (S1P)。 S1P 通过细胞表面受体对免疫和非免疫细胞产生多种细胞信号反应。该提案重点关注 S1P 类似物通过 S1P1R 和 S1P3R 对免疫细胞的细胞外影响以及肾脏炎症和损伤的细胞机制。我们的初步数据表明，S1P1R 激动剂的保护作用部分独立于 S1P 激动剂的典型效应——抑制淋巴细胞运输导致淋巴细胞减少，因为在缺乏 T、B 和NKT 细胞。因此，近端小管上皮细胞、内皮细胞或骨髓细胞（树突状细胞）上的 S1P1R 可以作为介导组织保护的重要细胞靶标。我们还发现，骨髓来源的 S1P3R 的缺失赋予了组织保护。这些数据以及 S1P1R 和 S1P3R 是肾脏中表达最丰富的 S1PR 的观察结果支持了目前关注这两种受体亚型在介导组织保护中的外在细胞功能的提议。我们假设：1）S1P1R 激活和 S1P3R 拮抗介导上皮细胞和内皮细胞的组织保护。 2)介导组织保护的理想新型化合物具有S1P1R的激动剂活性和S1P3R的拮抗剂活性。提出了三个目标：目标 1 检验上皮细胞和内皮细胞上的 S1P1R 激活介导近端小管组织保护的假设。目标 2 测试了以下假设：S1P1R 激活和 S1P3R 缺陷会减弱树突状细胞对 IRI 的先天免疫反应的激活，目标 3 测试了以下假设：具有 S1P1R 激动剂活性和 S1P3R 拮抗剂活性的新化合物是介导组织保护的理想特征。我们将使用野生型和转基因小鼠、嵌合小鼠、在易感转基因小鼠品系中使用白喉毒素的免疫细胞消融研究、过继转移研究和培养免疫细胞来解决体内和体外的机制问题。此外，我们的方法将结合免疫学、细胞生物学、分子和生理学工具来执行每个目标。我们的长期计划是更好地了解一类重要受体的作用，从而能够利用 S1P 受体化合物开发新的治疗干预措施，以阻止急性肾损伤的有害后果。