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.

项目总结/文摘

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