Early and Transient Activation of Fibroblast Promotes Tubule Repair after Acute Kidney Injury.

成纤维细胞的早期和短暂激活促进急性肾损伤后肾小管的修复。

• 批准号: 10223279
• 负责人: Dong Zhou
• 金额: $ 16.7万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223279
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Advisory Committees; Automobile Driving; Bioinformatics; Biomedical Research; Cells; Cellular biology; Cessation of life; Chronic Kidney Failure; Communication; Data; Development Plans; Dialysis procedure; Disease; Disease Progression; Early identification; Early treatment; Environment; Epithelial; Event; Feedback; Fibroblasts; Filtration; Fostering; Future; Goals; Growth Factor; HGF gene; Hour; Immunology; In Vitro; Injury to Kidney; Kidney; Kidney Diseases; Kidney Failure; Knockout Mice; Knowledge; Lead; MET gene; Mediating; Mentored Research Scientist Development Award; Mentors; Mesenchymal; Mus; Natural regeneration; Nephrology; Outcome; Pathogenesis; Pathology; Pharmacology; Phase; Phenotype; Play; Prevention; Process; Prognosis; Protease Domain; Proteomics; Regimen; Regulation; Renal tubule structure; Reporting; Research; Research Personnel; Role; SHH gene; Source; Structure; Testing; Therapeutic; Training; Tubular formation; Universities; Work; career; career development; cell type; conditional knockout; cost; design; epithelial repair; experience; experimental study; faculty research; health science research; in vivo; injury and repair; insight; interest; interstitial; kidney fibrosis; mouse model; multidisciplinary; novel; outcome prediction; prevent; programs; protective effect; renal damage; repaired; smoothened signaling pathway; therapeutic target

PROJECT SUMMARY/ABSTRACT Career Development Plan My primary career goal is to become a successful, independent investigator and leader in the field of kidney disease. To achieve my career goal, I have assembled an advisory committee from a multi-disciplinary group of established researchers at the University of Pittsburgh (Pitt). These researchers are experts in the fields of bioinformatics, pathology, cell biology, immunology, and nephrology. My career development plan includes personal mentoring, focused coursework, practical research experience, and professional training. Pitt is one of the nation’s most distinguished, comprehensive universities and a major center of biomedical research national wide. It is committed to fostering the careers of research faculty and maintains a strong and well- established health sciences research program. All these factors establish a positive environment in my career development towards independence. Research Plan Acute kidney injury (AKI) is an abrupt or rapid decline in renal filtration that happens within a few hours or a few days. Most of the work in the field focuses on renal tubule damage, but research on repair of the tubules and what process promotes surviving tubular epitheliums to dedifferentiate is lacking. Cellular events involved in the early phases of AKI and the triggers or sources responsible for tubule dedifferentiation remain unclear. As the cell neighbor to renal tubules, we believe activated fibroblasts play a main role in inducing renal tubule repair after AKI. Our recent preliminary studies show that multiple fibroblast phenotypes were activated as early as 1 hour and reach peak at 12 hours after AKI, which is far earlier than tubular epithelium proliferation. We previously recognized that in chronic kidney disease (CKD), a tubule-derived novel growth factor, Sonic Hedgehog (Shh), specifically targets interstitial fibroblast, driving renal fibrosis through epithelial-mesenchymal communication (EMC). In our AKI mouse model, Shh was also directly secreted by renal tubules and was upregulated as early as 1 hour in injured kidneys. To our surprise, compared to its role in CKD, Shh plays a completely opposite role in AKI; it has a protective effect in AKI. Pharmacological inhibition of Shh suppressed fibroblast activity and aggravated AKI. In cultured fibroblasts, Shh causes transient fibroblast activation and secretion of hepatocyte growth factor (HGF), which we reported to have a renoprotective role in AKI. Therefore, our central hypothesis is that renal tubule-derived Shh induces early and transient fibroblast activation to promote AKI repair through a Shh-HGF feedback loop. We will test this hypothesis in two specific aims: 1) Determine the mechanism of Shh-mediated EMC in promoting renal repair after AKI. 2) Determine the roles of the Shh-HGF feedback loop in renal repair after AKI. Fully understanding the early stages of AKI pathogenesis will be very beneficial in determining AKI prognosis and designing novel future therapeutic strategies.

项目总结/摘要 职业发展计划 我的主要职业目标是成为一名成功的独立研究者和肾脏领域的领导者。 疾病为了实现我的职业目标，我召集了一个来自多学科小组的咨询委员会 匹兹堡大学（皮特）的研究人员。这些研究人员是以下领域的专家： 生物信息学、病理学、细胞生物学、免疫学和肾脏学。我的职业发展计划包括 个人指导，重点课程，实践研究经验和专业培训。皮特就是其中之一 全国最杰出的综合性大学和生物医学研究的主要中心 全国范围内。它致力于促进研究教师的职业生涯，并保持一个强大的和良好的- 建立健康科学研究计划。所有这些因素都为我的职业生涯创造了一个积极的环境 向独立发展。 研究计划 急性肾损伤（阿基）是在几小时或几周内发生的肾滤过率突然或快速下降。 几天该领域的大部分工作集中在肾小管损伤上，但对肾小管修复的研究 缺乏促进存活肾小管上皮去分化的过程。涉及的细胞事件 在阿基的早期阶段，负责小管去分化的触发因素或来源仍然不清楚。 活化的成纤维细胞作为肾小管的近邻细胞，在诱导肾小管上皮细胞分化中起主要作用， 阿基后修复。我们最近的初步研究表明，多种成纤维细胞表型被激活， 阿基后1h达高峰，12 h达高峰，远早于肾小管上皮细胞增殖。 我们以前认识到，在慢性肾脏疾病（CKD），肾小管衍生的新的生长因子，声波， Hedgehog（Shh），特异性靶向间质成纤维细胞，通过上皮-间质细胞介导肾纤维化 通信（EMC）。在我们的阿基小鼠模型中，Shh也直接由肾小管分泌， 在损伤的肾脏中早在1小时就上调。令我们惊讶的是，与其在CKD中的作用相比，Shh扮演了一个 在阿基中起完全相反的作用;它对阿基有保护作用。Shh抑制的药理学抑制 成纤维细胞活性和加重的阿基。在培养的成纤维细胞中，Shh引起短暂的成纤维细胞活化， 肝细胞生长因子（HGF）的分泌，我们报告其在阿基中具有肾保护作用。因此，我们认为， 我们的中心假设是肾小管来源的Shh诱导早期和短暂的成纤维细胞活化， 通过Shh-HGF反馈环促进阿基修复。我们将在两个具体目标中检验这一假设： 确定Shh介导的EMC促进阿基后肾修复的机制。2)确定的角色 阿基后肾修复中的Shh-HGF反馈回路。充分了解阿基发病机制的早期阶段 将非常有益于确定阿基预后和设计新的未来治疗策略。