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一项探索肾脏纤维化发病机制的基础科学研究计划。为了实现这一目标，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，并在临床肾脏病学助理职位上获得了博士后奖学金计划，该计划以细胞外基质生物学为中心。目前的博士后研究是在拉古·卡鲁里博士的指导下进行的。他的实验室非常适合在现有的和新的分子技术以及转基因动物研究方面提供指导，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，以促进对肾脏损伤的保护，并将其用于设计保护肾脏免受慢性进行性肾脏疾病影响的治疗方法。这一建议的中心假设是，肾损伤的恢复遵循与调节肾脏发育的途径类似的途径。这种想法是基于之前的研究，这些研究表明，在肾脏发育过程中，骨形态发生蛋白-7(BMP-7)是一种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可能逆转上皮间充质转化(EMT)，涉及受损的肾小管上皮细胞，导致成纤维细胞的聚集。此外，BMP-7还诱导肾髓质成纤维细胞发生表型变化，类似于间充质向上皮细胞的转变，使上皮细胞重新形成。本申请中提出的研究目的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。

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.