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: 10203378
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203378
• 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; Epithelium; 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; 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; experience; experimental study; faculty research; health science research; in vivo; injury and repair; insight; interest; interstitial; kidney fibrosis; mouse model; multidisciplinary; novel; outcome forecast; 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.

项目摘要/摘要 职业发展计划 我的主要职业目标是成为肾脏领域一名成功的、独立的研究者和领导者。 疾病。为了实现我的职业目标，我组建了一个由多学科小组组成的咨询委员会 来自匹兹堡大学(匹兹堡)的知名研究人员。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、专注于课程、实践研究经验和专业培训。皮特就是其中之一 是美国最著名的综合性大学之一，也是生物医学研究的主要中心 全国范围内。它致力于培养研究人员的职业生涯，并保持强大和良好的- 制定健康科学研究计划。所有这些因素都为我的职业生涯创造了一个积极的环境 朝着独立的方向发展。 研究计划 急性肾损伤(AKI)是指肾脏滤过率突然或迅速下降，发生在几个小时或几个月内 几天。该领域的工作大多集中在肾小管损伤上，而对肾小管修复的研究较少。 目前尚缺乏促进存活的肾小管上皮细胞去分化的过程。涉及的细胞事件 在AKI的早期阶段，导致肾小管去分化的诱因或来源尚不清楚。 作为肾小管的近邻细胞，我们认为活化的成纤维细胞在诱导肾小管形成中起主要作用。 AKI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为 AKI后1h达高峰，12h达高峰，远早于肾小管上皮细胞的增殖。 我们先前认识到，在慢性肾脏疾病(CKD)中，一种新的小管源性生长因子Sonic Hedgehog(Shh)，特异性靶向间质成纤维细胞，通过上皮-间充质推动肾纤维化 通信(EMC)。在我们的AKI小鼠模型中，Shh也是由肾小管直接分泌的，并且是 损伤肾脏最早1小时表达上调。令我们惊讶的是，与其在CKD中的作用相比，Shh扮演着 在AKI中的作用完全相反；它在AKI中具有保护作用。Shh的药理抑制作用被抑制 成纤维细胞活性和AKI加重。在培养的成纤维细胞中，Shh引起成纤维细胞的瞬时激活和 分泌肝细胞生长因子(HGF)，我们报道它在AKI中具有肾脏保护作用。因此， 我们的中心假设是肾小管源性Shh诱导早期和短暂的成纤维细胞激活 通过Shh-HGF反馈循环促进AKI修复。我们将在两个具体目标中检验这一假设：1) 探讨Shh介导的EMC促进AKI后肾脏修复的机制。2)确定 Shh-HGF反馈环在急性肾损伤后肾修复中的作用充分认识AKI发病的早期阶段 对于判断AKI的预后和设计新的未来治疗策略将是非常有益的。