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

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。作为一名新加入康涅狄格州大学健康学院的初级教员，我组建了一个顾问委员会，成员来自 由康涅狄格州大学健康学院和皮特大学的资深研究人员组成的多学科小组。这些研究人员都是专家 在生物信息学、病理学、细胞生物学、免疫学和肾脏学领域。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知识。 训练。康涅狄格州大学健康学院和皮特大学是美国最杰出的综合性大学和专业 全国生物医学研究中心。他们致力于培养研究人员的职业生涯。 并保持强大和完善的健康科学研究计划。所有这些因素都建立了一个 在积极的环境下，我的职业发展走向独立。 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。

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.