Kidney Injury Molecule-1 in Epithelial Repair

肾损伤分子 1 在上皮修复中的作用

基本信息

批准号：
10686833
负责人：
JOSEPH VINCENT BONVENTRE
金额：
$ 54.79万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686833
关键词：
3-Dimensional Acute Acute Renal Failure with Renal Papillary Necrosis Affect Albumins Algorithms Anemia Animal Model Animals Antigen Presentation Architecture Autophagocytosis Binding Binding Sites Biological Markers Blood Canis familiaris Cardiovascular Diseases Cell Aging Cell Cycle Arrest Cell Line Cell Separation Cells Characteristics Chronic Chronic Kidney Failure Clinical Clinical Trials Complex Cryoelectron Microscopy Cytoskeleton DNA Damage Development Diabetic Nephropathy Diabetic mouse Drug Targeting Endocytosis Epithelial Cells FRAP1 gene Family suidae Fatty Acids Fibronectins Fibrosis Functional disorder G2/M Arrest Generations Genetic Models Goals Grant Heart Hypertrophy Hemodialysis Human Hypertension Impairment Inflammation Inflammatory Inflammatory Response Injury Injury to Kidney Integrins Ischemia Kidney Kidney Failure Link Lymphoid Tissue MAP Kinase Gene Mediating Mitochondria Modeling Molecular Monoclonal Antibodies Mucins Mus Myofibroblast NF-kappa B Nonesterified Fatty Acids Nuclear Organ failure Organoids Oxidants PIK3CG gene Palmitates Palmitic Acids Pathway interactions Phagocytes Phagocytosis Phagosomes Phenotype Plasma Play Population Process Production Proteins Proximal Kidney Tubules Qualifying Rattus Regulation Regulatory T-Lymphocyte Renal Cell Carcinoma Reporting Rodent Role Secondary Hypertension Signal Transduction Structure System Time Tissues Toxic effect Transplantation Tubular formation Up-Regulation Urine Zebrafish absorption cell dedifferentiation cell injury energy balance epithelial repair extracellular fatty acid oxidation fatty acid-binding proteins glomerular filtration human pluripotent stem cell inhibition of autophagy inhibitor injured interstitial kidney epithelial cell man mitochondrial dysfunction mouse genetics mouse model mutant nephrotoxicity non-diabetic novel oxidized lipid oxidized low density lipoprotein phosphatidylserine receptor polyclonal antibody pre-clinical prevent rat KIM-1 protein repaired response reuptake safety study screening senescence side effect small molecule libraries therapeutic target uptake urinary

项目摘要

Project Summary/ Abstract Kidney Injury Molecule-1 (KIM-1) is the most upregulated protein in proximal tubular epithelial cells in various states characterized by epithelial cell dedifferentiation: ischemia, toxic renal injury, and renal cell carcinoma. We have cloned, generated cells and animals expressing wild-type and mutant KIM-1, and created monoclonal and polyclonal antibodies to, human, mouse, rat, pig, dog, and zebrafish KIM-1. We have reported that the KIM-1 ectodomain is cleaved into the blood and urine of subjects with acute (AKI) and chronic (CKD) kidney injury and is a sensitive and specific kidney injury biomarker to detect kidney injury and predict progression of CKD. KIM-1 has been qualified by the FDA for preclinical and clinical use in kidney safety studies. We have discovered that KIM-1 transforms kidney epithelial cells into semiprofessional phagocytes making it the first nonmyeloid phosphatidylserine receptor. We have described a novel phagocytosis pathway that links autophagy to KIM-1-mediated phagosome maturation and MHC restricted antigen presentation in epithelial cells. We have shown that KIM-1 expression in early AKI is adaptive, but chronic expression leads to CKD with severe fibrosis, secondary hypertension, and cardiac hypertrophy. A mouse lacking the extracellular mucin domain, important for phagocytosis, is protected against development of fibrosis. We have found that KIM-1 mediates uptake of palmitate-bound albumin and recently found an inhibitor of KIM-1- mediated phagocytosis by screening a small molecule library. The inhibitor reduces cell lipotoxicity and fibrosis in a novel mouse model of diabetic kidney disease. The current competing renewal application builds upon and extends our prior findings. Our goal is to further characterize KIM-1-mediated uptake of fatty acid bound albumin (FA-Albumin), and the implications of this uptake for cellular injury and maladaptive repair, including cell senescence leading to profibrotic and proinflammatory responses that ultimately lead to progressive CKD. KIM-1 may be a drug target to prevent and treat CKD. We hypothesize that persistent KIM-1-mediated endocytosis of FA-Albumin and subsequent signaling leads to toxicity. FA-Albumin uptake leads to a mitochondrial dysfunction, DNA damage response (DDR), G2/M arrest, mTOR signaling, TASCC formation, and a prosecretory fibrotic phenotype. In addition KIM-1-FA-Albumin uptake leads to chronic tissue inflammation in part due to tertiary lymphoid tissue development through LTaβ/LTβR signaling. In Specific Aim 1 we will characterize binding of KIM-1 to FA-Albumin and determine the architecture, structural dynamics and molecular basis for FA-Albumin binding to KIM-1. In Specific Aim 2 we will characterize the intracellular consequences of KIM-1 mediated FA-Albumin endocytosis, particularly on mitochondrial function, DNA damage, the DDR, cell cycle arrest and the profibrotic secretome. In Specific Aim 3 we will evaluate the role of KIM-1 mediated FA- Albumin uptake and DDR in LTaβ/LTβR signaling leading to tertiary lymphoid tissue (TLT) formation with consequent pro-inflammatory consequences in animal models of AKI to CKD transition.

项目概要/摘要肾损伤分子-1 (KIM-1) 是多种疾病中近端肾小管上皮细胞中表达最上调的蛋白。以上皮细胞去分化为特征的状态：缺血、中毒性肾损伤和肾细胞癌。我们克隆、生成了表达野生型和突变型 KIM-1 的细胞和动物，并创建了单克隆抗体我们已经报道了针对人、小鼠、大鼠、猪、狗和斑马鱼 KIM-1 的多克隆抗体。 KIM-1 胞外域被裂解进入急性 (AKI) 和慢性 (CKD) 肾病受试者的血液和尿液中损伤，是一种敏感且特异的肾损伤生物标志物，用于检测肾损伤并预测肾损伤的进展 CKD. KIM-1 已获得 FDA 批准用于肾脏安全性研究的临床前和临床。发现 KIM-1 将肾上皮细胞转化为半专业吞噬细胞，使其成为我们描述了第一个非髓样磷脂酰丝氨酸受体。自噬对 KIM-1 介导的吞噬体成熟和 MHC 限制上皮抗原呈递我们已经证明早期 AKI 中的 KIM-1 表达是适应性的，但慢性表达会导致患有严重纤维化、继发性高血压和心脏肥大的 CKD 小鼠。细胞外粘蛋白结构域对于吞噬作用很重要，可以防止纤维化的发展。发现 KIM-1 介导棕榈酸酯结合白蛋白的摄取，并且最近发现了 KIM-1 的抑制剂- 该抑制剂通过筛选小分子库介导吞噬作用，从而降低细胞脂毒性和糖尿病肾病新型小鼠模型中的纤维化当前竞争的更新应用程序构建。我们的目标是进一步表征 KIM-1 介导的脂肪酸摄取。结合白蛋白（FA-白蛋白），以及这种摄取对细胞损伤和适应不良修复的影响，包括细胞衰老导致促纤维化和促炎症反应，最终导致进行性 CKD 可能是预防和治疗 CKD 的药物靶点。 KIM-1 介导的 FA-白蛋白内吞作用和随后的信号传导导致毒性。摄取导致线粒体功能障碍、DNA 损伤反应 (DDR)、G2/M 期停滞、mTOR 此外，KIM-1-FA-白蛋白还包括信号传导、TASCC 形成和原分泌性纤维化表型。摄取导致慢性组织炎症，部分原因是三级炎症在具体目标 1 中，我们将描述通过 LTaβ/LTβR 信号传导的淋巴组织发育。 KIM-1 与 FA-白蛋白的结合并确定其结构、结构动力学和分子基础 FA-白蛋白与 KIM-1 的结合在特定目标 2 中，我们将描述 KIM-1 的细胞内后果。介导 FA-白蛋白内吞作用，特别是线粒体功能、DNA 损伤、DDR、细胞周期在特定目标 3 中，我们将评估 KIM-1 介导的 FA- 的作用。 LTaβ/LTβR 信号传导中的白蛋白摄取和 DDR 导致三级淋巴组织 (TLT) 形成在 AKI 向 CKD 转变的动物模型中产生随之而来的促炎症后果。

项目成果

期刊论文数量（149）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Next-generation biomarkers for detecting kidney toxicity.

DOI：
10.1038/nbt0510-436
发表时间：
2010-05
期刊：
NATURE BIOTECHNOLOGY
影响因子：
46.9
作者：
Bonventre, Joseph V.;Vaidya, Vishal S.;Schmouder, Robert;Feig, Peter;Dieterle, Frank
通讯作者：
Dieterle, Frank

Differences in immunolocalization of Kim-1, RPA-1, and RPA-2 in kidneys of gentamicin-, cisplatin-, and valproic acid-treated rats: potential role of iNOS and nitrotyrosine.

DOI：
10.1177/0192623309339605
发表时间：
2009-08
期刊：
Toxicologic pathology
影响因子：
1.5
作者：
Zhang J;Goering PL;Espandiari P;Shaw M;Bonventre JV;Vaidya VS;Brown RP;Keenan J;Kilty CG;Sadrieh N;Hanig JP
通讯作者：
Hanig JP

Circulating Kidney Injury Molecule 1 Predicts Prognosis and Poor Outcome in Patients With Acetaminophen-Induced Liver Injury.

DOI：
10.1002/hep.27857
发表时间：
2015-08
期刊：
Hepatology (Baltimore, Md.)
影响因子：
0
作者：
Antoine DJ;Sabbisetti VS;Francis B;Jorgensen AL;Craig DG;Simpson KJ;Bonventre JV;Park BK;Dear JW
通讯作者：
Dear JW

Effect of renin-angiotensin-aldosterone system inhibition, dietary sodium restriction, and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease: a post hoc analysis of a randomized controlled trial.

DOI：
10.1053/j.ajkd.2008.07.021
发表时间：
2009-01
期刊：
American journal of kidney diseases : the official journal of the National Kidney Foundation
影响因子：
0
作者：
Waanders F;Vaidya VS;van Goor H;Leuvenink H;Damman K;Hamming I;Bonventre JV;Vogt L;Navis G
通讯作者：
Navis G

Kidney injury molecule-1 is an early noninvasive indicator for donor brain death-induced injury prior to kidney transplantation.

肾损伤分子-1 是肾移植前供体脑死亡引起的损伤的早期非侵入性指标。

DOI：
10.1111/j.1600-6143.2009.02713.x
发表时间：
2009
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
0
作者：
Nijboer,WN;Schuurs,TA;Damman,J;vanGoor,H;Vaidya,VS;vanderHeide,JJHoman;Leuvenink,HGD;Bonventre,JV;Ploeg,RJ
通讯作者：
Ploeg,RJ