Understanding the Function of Tamm-Horsfall Protein in Acute kidney Injury.

了解 Tamm-Horsfall 蛋白在急性肾损伤中的功能。

• 批准号: 10160893
• 负责人: Tarek Maurice Ashkar
• 金额: $ 35.53万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160893
• 关键词: Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Animal Model; Apical; Biological; Blood Circulation; Bone Marrow; Cell Line; Cells; Chromatography; Chronic Kidney Failure; Closure by clamp; Complex; Confocal Microscopy; Data; Deterioration; Disease; Elements; Epithelial; Flow Cytometry; Foundations; Functional disorder; Future; Goals; Granulopoiesis; Homeostasis; Homing; Human; Immunofluorescence Immunologic; In Vitro; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Interleukin-17; Ischemia; Kidney; Kidney Failure; Knock-out; Knowledge; Lasers; Length of Stay; Limb structure; Link; Mass Spectrum Analysis; Mediating; Microdissection; Molecular; Morbidity - disease rate; Mortality Determinants; Neutrophil Infiltration; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmacodynamics; Predisposition; Production; Protein Deficiency; Proteins; Publishing; Recovery; Renal function; Reperfusion Injury; Reperfusion Therapy; Research; Role; Signal Pathway; Signal Transduction; Structure of ascending limb of Henle' s loop; Techniques; Testing; Therapeutic; Therapeutic Uses; Thick; Time; Tubular formation; UMOD gene; Urine; Western Blotting; Wild Type Mouse; Work; experience; experimental study; improved outcome; inhibitor/antagonist; innovation; interleukin-23; intravital microscopy; ischemic injury; kidney cell; mortality; neutrophil; novel; renal ischemia; therapy development; tool; urinary

Acute kidney injury (AKI) is a major determinant of mortality and morbidity in hospitalized patients. Understanding the pathophysiology of AKI is essential for the development of therapy. This application proposes to study the role of Tamm-Horsfall protein (THP) in AKI. This protein is expressed exclusively in the kidney by cells of the thick ascending limbs (TAL) of Henle. In the last few years, we uncovered a key role of THP in mediating a protective tubular cross-talk in AKI. We showed that THP regulates inflammatory signaling and injury to S3 segments, which are neighboring tubules to TAL in the kidney outer medulla. The immediate goal of the current proposal is to study the importance of the interaction of THP with S3 segments in regulating neutrophil infiltration and limiting oxidative stress in AKI. These studies will form the basis to transition into therapeutic applications. Indeed, the PI's long term goal is to understand how the role of THP can be modulated to treat patients who develop AKI. The central hypothesis is that Tamm-Horsfall protein regulates the inflammatory response triggered by ischemic injury in the outer medulla; an effect that requires an interaction of THP with the surrounding tubular elements. This hypothesis has been formulated on the basis of strong preliminary and published data. The following specific aims will be used to investigate this hypothesis. Aim 1 will investigate the role of THP as a key regulator of neutrophil infiltration in the kidney after AKI. Aim 2 will study the functional significance of the interaction of THP with neighboring epithelium in kidney injury Aim 2 will investigate therapeutic modulation of THP to inhibit neutrophil influx and promote recovery after AKI This research will involve the use of THP knockout and wild type mice. The animal model used for AKI is renal ischemia-reperfusion injury achieved through renal pedicle clamping. In vitro studies will involve cell lines for proximal tubules. Other techniques used in this work include: Immunofluorescence laser micro-dissection of specific tubular sections, Immunofluoresence confocal and intravital microscopy, flow cytometry, real time- PCR, western blot, various forms of chromatography and mass spectrometry. This research is innovative, because it will uncover novel regulatory functions for THP that may be relevant not only in kidney injury but also in other forms of acute or chronic renal disease. Future strategies that enhance the role of THP in the kidney will be of important therapeutic significance.

急性肾脏损伤（AKI）是住院患者死亡率和发病率的主要决定因素。 了解AKI的病理生理学对于发展治疗至关重要。此应用程序 提议研究塔姆 - 霍尔斯秋季蛋白（THP）在AKI中的作用。该蛋白仅在 肾脏的细胞肾脏较厚的肢体（tal）。在过去的几年中，我们发现了 THP介导AKI的保护性管状串扰。我们表明THP调节炎症信号传导 S3段的损伤是肾脏外髓质中附近的小管。直接 当前建议的目标是研究THP与S3段相互作用在调节中的重要性 中性粒细胞浸润和限制AKI中的氧化应激。这些研究将构成过渡到 治疗应用。确实，PI的长期目标是了解THP的作用如何 调节以治疗发展为AKI的患者。 中心假设是tamm-horsfall蛋白调节由 外髓质缺血性损伤；需要THP与周围管状相互作用的效果 元素。该假设是根据强大的初步和公开数据提出的。这 以下特定目标将用于研究这一假设。 AIM 1将研究THP作为AKI后肾脏中嗜中性粒细胞浸润的关键调节剂的作用。 AIM 2将研究THP与肾脏上皮相互作用的功能意义 受伤 AIM 2将研究THP的治疗调节以抑制中性粒细胞流入并促进AKI后恢复 这项研究将涉及使用THP敲除和野生型小鼠。用于AKI的动物模型是肾脏 通过肾椎弓根夹具造成的缺血再灌注损伤。体外研究将涉及细胞系 近端小管。这项工作中使用的其他技术包括：免疫荧光激光微截止 特定的管状切片，免疫荧光共焦和插入式显微镜，流式细胞仪，实时 - PCR，Western印迹，各种形式的色谱和质谱法。 这项研究具有创新性，因为它将发现可能与之相关的新型调节功能 仅在肾脏损伤中，还处于其他形式的急性或慢性肾脏疾病中。提高未来的策略 THP在肾脏中的作用将具有重要的治疗意义。