Re-Induction of Developmental Programs during Chronic Renal Injury

描述（由申请人提供）： 首席研究员的长期目标是指导探索肾纤维化发病机制的基础科学研究项目。为了实现这一目标，他参加了一个博士后奖学金项目，该项目以细胞外基质生物学为中心，此前他在德国哥廷根大学接受了肾成纤维细胞和肾小管上皮细胞生物学的研究培训，并担任了临床肾病学见习。目前的博士后奖学金研究是在Raghu Kaghui博士的监督下进行的。他的实验室非常适合为建立和新的分子技术和转基因动物研究提供指导，以促进独立职业生涯的开始。这里提出的研究项目集中在探索内源性再生机制，这有助于保护肾损伤及其在设计治疗方法中的应用，以保护肾脏免受慢性进行性肾脏疾病的影响。该建议的中心假设是，肾损伤的恢复遵循与介导肾脏发育的途径相似的途径。这种想法是基于以前的研究，这些研究表明，骨形态发生蛋白-7（BMP-7），一种在肾脏发育过程中参与小管形成的生长因子，有助于慢性肾脏疾病的消退。这些先前的研究表明，BMP-7可以逆转上皮间质转化（EMT），涉及受损的肾小管上皮细胞，导致成纤维细胞的积累。此外，BMP-7还诱导髓质肾成纤维细胞的表型变化，类似于间充质向上皮转化，使上皮细胞再生。本申请中提出的研究目标集中在测试成纤维细胞在肾损伤修复中的潜在作用，并试图在分子水平上进一步分析初步的表型观察结果。

DESCRIPTION (provided by applicant): The Principal Investigator's long-term goal is to direct a basic science research program exploring the pathogenesis of kidney fibrosis. To achieve this goal he has entered a post-doctoral fellowship program, which is centered around extracellular matrix biology following his research training in renal fibroblast and tubular epithelial cell biology coupled with a clinical Nephrology clerkship at the University of Goettingen in Germany. The current postdoctoral fellowship research is conducted under supervision of Dr. Raghu Kalluri. His laboratory is well suited to provide guidance in established and new molecular techniques and transgenic animal studies to foster the start of an independent career. The research project proposed here centers on exploring endogenus regenerative mechanisms, which facilitate protection from kidney injury and its use in designing therapies to protect the kidney from chronic progressive kidney disease. The central hypothesis of this proposal is that the recovery from renal injury follows pathways, which are similar to those, which mediate kidney development. Such thinking is based on previous studies, which demonstrate that administration of bone morphogenic protein-7 (BMP-7), a growth factor involved in tubulogenesis during kidney development, facilitates regression of chronic kidney disease. These previous studies suggest that BMP-7 may reverse epithelial to mesenchymal transition (EMT) involving injured tubular epithelial cells, leading to accumulation of fibroblasts. Additionally, BMP-7 also induces phenotypic changes in medullary renal fibroblasts resembling mesenchymal to epithelial transition, regenrating epithelial cells. The study aims proposed in this application are centered around testing the potential role of fibroblasts in the repair of renal injury and they attempt to further analyze the preliminary phenotypic observation at a molecular level.