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: 10435597
• 负责人: Dong Zhou
• 金额: $ 8.35万
• 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/10435597
• 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; Faculty; Feedback; Fibroblasts; Filtration; Fostering; Future; Goals; Growth Factor; HGF gene; Health; 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. As a junior faculty newly joined UCONN Health, I have assembled an advisory committee from a multi-disciplinary group of established researchers at UCONN Health and 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. UCONN Health and Pitt are the nation’s most distinguished, comprehensive universities and major centers of biomedical research national wide. They are committed to fostering the careers of research faculty and maintain 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的成功，独立的调查员和领导者 疾病。作为初级教师新加入UConn Health，我已经组建了一个咨询委员会 UConn Health and Pitt的成熟研究人员的多学科小组。这些研究人员是专家 在生物信息学，病理学，细胞生物学，免疫学和肾脏科领域。我的职业发展 计划包括个人心理，专注的课程，实践研究经验和专业 训练。 UConn Health和Pitt是美国最杰出，最全面的大学和主要的大学 全国生物医学研究中心。他们致力于培养研究教师的职业 并保持一项强大且成熟的健康科学研究计划。所有这些因素建立了一个 我职业发展的积极环境。 研究计划 急性肾脏损伤（AKI）是肾过滤的突然或迅速下降，发生在几个小时之内或 几天。该领域的大多数工作都集中在肾小管损伤上，但是有关维修的研究 缺乏哪种过程促进生存管状上皮以去分化。涉及细胞事件 在AKI的早期阶段，以及负责小管去分化的触发因素或来源尚不清楚。 作为肾小管的细胞邻居，我们认为活化的成纤维细胞在诱导的肾小管中起主要作用 AKI后修理。我们最近的初步研究表明，多个成纤维细胞表型被激活为 早在1小时内，在AKI后12小时达到峰值，远比管状上皮增殖早得多。 我们以前认识到，在慢性肾脏疾病（CKD）中，它是一个衍生的新型生长因子，声音 刺猬（SHH），特别针对间质成纤维细胞，通过上皮 - 间质推动肾纤维化 通信（EMC）。在我们的AKI鼠标模型中，SHH还直接由肾小管分泌 受伤的肾脏最早在1小时内上调。令我们惊讶的是，与其在CKD中的作用相比，SHH扮演 在AKI中的作用完全相反；它在AKI中具有保护作用。抑制SHH的药理抑制 成纤维细胞活性和汇总的AKI。在培养的成纤维细胞中，SHH引起短暂的成纤维细胞激活和 肝细胞生长因子（HGF）的分泌，我们据报道在AKI中具有肾脏保护作用。所以， 我们的中心假设是肾管衍生的SHH早期诱导成纤维细胞激活 通过SHH-HGF反馈循环促进AKI维修。我们将以两个具体目的测试这一假设：1） 确定SHH介导的EMC在AKI后促进肾脏修复方面的机制。 2）确定 AKI后，肾脏修复中的SHH-HGF反馈回路。完全了解AKI发病机理的早期阶段 在确定AKI预后和设计新颖的未来治疗策略方面将非常有益。

项目成果

Sonic hedgehog connects podocyte injury to mesangial activation and glomerulosclerosis.

• DOI: 10.1172/jci.insight.130515
• 发表时间: 2019-11
• 期刊: JCI insight
• 影响因子: 8
• 作者: Dong Zhou;H. Fu;Yang Han;Lu Zhang;Shijia Liu;Lin Lin-Lin;D. Stolz;Youhua Liu