The formation of kidney local microenvironment after acute kidney injury.

急性肾损伤后肾脏局部微环境的形成

基本信息

批准号：
10195384
负责人：
Dong Zhou
金额：
$ 12.3万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
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：
2021-02-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10195384
关键词：
3-Dimensional Acute Renal Failure with Renal Papillary Necrosis Affect Animal Model Attention Binding Biological Cell Communication Cell Proliferation Cells Cessation of life Chronic Kidney Failure Complex Creatinine Data Deterioration Disease Environment Event Extracellular Domain Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Future Glues Glycoproteins Growth Factor Hospitalization Immunoprecipitation In Vitro Injury Injury to Kidney Kidney Knowledge Ligands Mediating Mentored Research Scientist Development Award Modeling Morbidity - disease rate Mus Output Pathogenesis Process Proteins Proteomics Regimen Regulation Renal function Renal tubule structure Reporting Research Research Personnel Resources Risk Role SHH gene Serum Structure System Techniques Testing Time Tubular formation Urine Vertebral column base cost design experience in vivo injured injury and repair kidney repair knock-down mortality new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression prevent recruit repaired scaffold tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) is characterized by abrupt deterioration in kidney function, manifested by an increase in serum creatinine level, with or without a reduction in the amount of urine output. In the US, there was close to one million AKI hospitalizations in 2000, and this number quadrupled by 2014. The morbidity, mortality, and costs of AKI are far greater than formerly acknowledged. Regardless of the initial causes of AKI, renal tubules are considered to be the epicenter of damage. Little attention is paid to the changes of the renal local microenvironment in AKI, although the concept of a ‘microenvironment’ has already shaped our understanding of the pathogenesis of various diseases. The kidney microenvironment in AKI is comprised of different cellular components such as injured tubular cells, activated fibroblasts, extracellular matrix (ECM), and a variety of secreted factors. In general, after AKI, renal tubules undergo a repair process of dedifferentiation. During this process, ECM is an indispensable component in organizing a favorable microenvironment to promote tubule repopulation. To further understand the role of ECM in the formation of the kidney microenvironment, we constructed an ischemic kidney injury model at 10 different time points, from day 0 to 10. By using proteomics, we found that extracellular matrix protein 1 (ECM1) was the earliest activated matrix protein after ischemic AKI. We then experimentally confirmed that ECM1 was induced rapidly, as early as 4-8h after AKI, and it predominantly localizes at the foci rich in fibroblasts. In the kidney, the fibroblast is the major cellular resource of ECM synthesis. The data generated by my K01 award revealed that, in AKI, fibroblast activation is a superior early event, and it occurs far earlier than tubular cell proliferation. Meanwhile, a tubule-derived novel growth factor, Sonic Hedgehog (Shh) was secreted by renal tubules and specifically targets fibroblasts. By immunoprecipitation, we found that ECM1 can bind to the Shh ligand in vitro. Based on these findings, we hypothesized that after AKI, ECM1 directly recruits Shh to form a favorable microenvironment to promote kidney remodeling.We will test this hypothesis in two specific aims: 1) Determine the mechanistic role of ECM1 in microenvironment formation ex vivo. 2) Determine the role of the ECM1-organized microenvironment in promoting AKI repair in vivo. The data generated from this application will have wide implications in comprehending the pathogenesis of kidney repair and in designing novel therapeutic regimens for AKI treatment.

项目概要/摘要急性肾损伤（AKI）的特点是肾功能突然恶化，表现为肾功能增加在美国，无论是否减少尿量，血清肌酐水平都接近。 2000 年，AKI 住院人数达到 100 万人，到 2014 年，这一数字翻了两番。发病率、死亡率和无论 AKI、肾小管的最初原因如何，AKI 造成的损失都远远大于以前所承认的。被认为是损害的中心，但很少关注肾脏局部的变化。 AKI 中的微环境，尽管“微环境”的概念已经形成了我们的理解 AKI 中的肾脏微环境由不同的细胞组成。受损的肾小管细胞、活化的成纤维细胞、细胞外基质 (ECM) 和多种成分一般来说，AKI 后，肾小管会经历去分化的修复过程。过程中，ECM是组织促进小管生长的有利微环境不可或缺的组成部分为了进一步了解 ECM 在肾脏微环境形成中的作用，我们在第 0 天到第 10 天的 10 个不同时间点构建了缺血性肾损伤模型。通过使用蛋白质组学，我们发现细胞外基质蛋白1（ECM1）是缺血性AKI后最早激活的基质蛋白。然后我们通过实验证实 ECM1 早在 AKI 后 4-8 小时就被迅速诱导，并且主要位于富含成纤维细胞的部位，在肾脏中，成纤维细胞是主要的细胞资源。我的 K01 奖生成的数据表明，在 AKI 中，成纤维细胞激活是一个早期事件，而且它发生的时间远远早于肾小管细胞增殖，同时是肾小管衍生的新现象。生长因子 Sonic Hedgehog (Shh) 由肾小管分泌，专门针对成纤维细胞。免疫沉淀，我们发现 ECM1 可以在体外与 Shh 配体结合。 AKI后，ECM1直接招募Shh以形成有利的微环境促进肾脏重塑。我们将在两个具体目标中检验这一假设：1）确定机制 ECM1在离体微环境形成中的作用2)确定ECM1组织的作用。该应用产生的数据将具有广泛的促进体内 AKI 修复的微环境。对理解肾脏修复发病机制和设计新治疗方案的意义用于 AKI 治疗。