Kidney Injury Molecule-1 in Epithelial Repair

肾损伤分子 1 在上皮修复中的作用

• 批准号: 8097546
• 负责人: JOSEPH VINCENT BONVENTRE
• 金额: $ 40.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097546
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Age-Months; Anemia; Animals; Apoptotic; Autoantigens; Autophagocytosis; Autophagosome; Binding; Biological Markers; Blood flow; Canis familiaris; Cardiac Death; Cell Cycle Arrest; Cell Death; Cell membrane; Cell surface; Cells; Cellular Stress; Cessation of life; Characteristics; Chronic; Chronic Kidney Failure; Cisplatin; Cleaved cell; Clinical; Complementary DNA; Control Animal; Defect; Dendritic Cells; Disease; Down-Regulation; Epithelial; Epithelial Cells; Epithelium; Exposure to; Extracellular Domain; Family suidae; Fibrosis; Functional disorder; Generations; Genes; Goals; Heart Hypertrophy; Heat shock proteins; Human; Human Cloning; Immune response; Immune system; Immunoglobulins; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Lead; Learning; Ligands; M cell; Malignant - descriptor; Mediating; Mediator of activation protein; Membrane Glycoproteins; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Movement; Mucins; Mus; Mutant Strains Mice; Mutation; Myeloid Cells; Necrosis; Organ; Patients; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Phenotype; Process; Progressive Disease; Property; Proteins; Proteolysis; Qualifying; Rattus; Recovery; Regulation; Renal Cell Carcinoma; Renal tubule structure; Reperfusion Therapy; Rodent; Role; Surface; T-Cell Activation; Therapeutic Intervention; Time; Tissues; Toll-like receptors; Toxin; Transgenic Animals; Transgenic Mice; Tubular formation; Type I Epithelial Receptor Cell; Tyrosine Phosphorylation; Uremia; Urine; Work; Zebrafish; base; calreticulin; cell dedifferentiation; cell injury; disease phenotype; endoplasmic reticulum stress; extracellular; human HAVCR1 protein; immunogenicity; injured; injury and repair; insight; interest; kidney epithelial cell; macrophage; macrophage scavenger receptors; mortality; mutant; novel; novel therapeutics; oxidized low density lipoprotein; phagocytosis receptor; phosphatidylserine receptor; polyclonal antibody; preclinical safety; prevent; protein function; public health relevance; rat KIM-1 protein; receptor expression; repaired; representational difference analysis; response; safety study; scavenger receptor; senescence; stress protein; therapeutic target; uptake

DESCRIPTION (provided by applicant): Kidney injury molecule-1 (KIM-1) is the most up regulated 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, and generated monoclonal and polyclonal antibodies to, the human, mouse, pig, dog, zebrafish and rat KIM-1. The KIM-1 ectodomain is cleaved and found in the urine of patients with acute kidney injury or renal cell carcinoma and is a sensitive and specific biomarker for kidney injury qualified by the FDA for preclinical safety studies and currently used in many clinical safety studies. We have discovered that KIM-1 transforms kidney epithelial cells into semiprofessional phagocytes making it the first nonmyeloid phosphatidylserine receptor. A mutant mouse lacking an extracellular domain that is important for phagocytosis and a transgenic mouse with Kim-1 expression in the renal tubule have important phenotypes supporting a critical role for this protein in acute and chronic kidney disease. The goal of this proposal is to further characterize the functional role of KIM-1 during acute and chronic injury to the kidney. We hypothesize that KIM-1 reduces the early inflammatory response to ischemic injury as it mediates uptake of apoptotic and necrotic debris from the damaged proximal tubule. In Specific Aim 1 we will characterize and evaluate the phagocytic function of KIM-1 in protection of the kidney exposed to ischemia or toxins. A mutant mouse that is defective in phagocytosis sustains increased injury to the kidney in response to ischemia or cisplatin. The effects of Kim-1 on autophagy, inflammation and the innate immune response will be explored. The contributions of various extracellular and intracellular domains of KIM-1 on phagocytosis and autophagy will be evaluated. In our second specific aim we will explore our hypothesis that KIM-1's interactions with calreticulin on the cell surface of apoptotic and necrotic cell modulate the immunogenicity of cell death associated with acute kidney injury. A considerable number of patients with chronic kidney disease have elevated levels of KIM-1 protein in their urine and kidney tissue. In the third Specific Aim we will analyze the role of persistent KIM-1 expression on inflammation and chronic fibrosis. We have created a transgenic mouse which expresses low levels of Kim-1 in the kidney tubule. This mouse develops severe tubulointerstitial inflammatory disease, anemia, and cardiac hypertrophy and dies at 4-6 months of age with chronic renal failure. This is a novel model of chronic kidney disease and we hypothesize that chronic KIM-1 expression is maladaptive. We will explore the molecular processes responsible for this impressive kidney disease phenotype including the role of chronic KIM-1 expression in cell cycle arrest. In summary understanding the function of KIM-1 will provide important insight into the role of this protein in injury and repair processes of the kidney, and may identify KIM-1 as an important therapeutic target not only for acute and chronic renal disease but also for malignant transformation of the epithelial cell. PUBLIC HEALTH RELEVANCE: Our goal is to understand how the kidney is able to repair itself after sustaining damage due to temporary reductions in blood flow or exposures to drugs which may injure the kidney. This work also is directed at learning how abnormal repair in the kidney can lead to progressive disease resulting in kidney failure. The work hopefully will lead to new understandings that can be used to develop new therapeutic drugs that can enhance recovery of the kidney when it is injured and prevent progression of kidney disease.

描述（由申请人提供）：肾损伤分子-1（KIM-1）是由上皮细胞去分化特征的各种状态近端管状上皮细胞中最高的蛋白质：缺血，毒性肾损伤和肾细胞癌。我们已经克隆并产生了与人，小鼠，猪，狗，斑马鱼和大鼠KIM-1的单克隆和多克隆抗体。 Kim-1外生域在急性肾脏损伤或肾细胞癌的尿液中被切割并发现，是FDA资格用于临床前安全研究的肾脏损伤的敏感且特异性的生物标志物，目前在许多临床安全研究中使用。我们已经发现KIM-1将肾上皮细胞转化为半型吞噬细胞，使其成为第一个非甲状腺磷脂酰丝氨酸受体。缺乏细胞外域的突变小鼠对吞噬作用很重要，在肾小管中具有KIM-1表达的转基因小鼠具有重要的表型，具有重要的表型，支持该蛋白质在急性和慢性肾脏疾病中的关键作用。该提议的目的是进一步表征KIM-1在肾脏急性损伤中的功能作用。我们假设KIM-1减少了对缺血性损伤的早期炎症反应，因为它介导了受损的近端小管中凋亡和坏死碎片的摄取。在特定目标1中，我们将表征和评估KIM-1在保护暴露于缺血或毒素的肾脏中的吞噬功能。在吞噬作用中有缺陷的突变小鼠因缺血或顺铂而导致肾脏的损伤增加。 KIM-1对自噬，炎症和先天免疫反应的影响。将评估KIM-1各种细胞外和细胞内结构域对吞噬和自噬的贡献。在我们的第二个特定目的中，我们将探讨我们的假设，即Kim-1与凋亡和坏死细胞细胞表面上的钙网蛋白相互作用调节与急性肾脏损伤有关的细胞死亡的免疫原性。大量慢性肾脏疾病患者的尿液和肾脏组织中KIM-1蛋白水平升高。在第三个特定目的中，我们将分析持续的KIM-1表达在炎症和慢性纤维化中的作用。我们创建了一种转基因小鼠，该小鼠在肾小管中表达较低水平的KIM-1。该小鼠会出现严重的肾小球炎症性疾病，贫血和心脏肥大，并在4-6个月大时死亡，死于慢性肾衰竭。这是一种慢性肾脏疾病的新型模型，我们假设慢性KIM-1表达是适应不良的。我们将探索负责这种令人印象深刻的肾脏疾病表型的分子过程，包括慢性KIM-1表达在细胞周期停滞中的作用。总而言之，KIM-1的功能将为该蛋白在肾脏的损伤和修复过程中的作用提供重要的见解，并且可以将KIM-1识别为重要的治疗靶标，不仅是急性和慢性肾脏疾病的重要治疗靶标，而且是上皮细胞的恶性转化。 公共卫生相关性：我们的目标是了解肾脏在暂时减少血液流量或可能伤害肾脏的药物的损害后能够修复自身。这项工作还旨在学习肾脏中的异常修复如何导致肾脏衰竭。希望这项工作将导致新的理解，可用于开发新的治疗药物，这些药物在受伤时可以增强肾脏的恢复并防止肾脏疾病的进展。