Kidney Injury Molecule-1 in Renal Fibrosis

这份提案描述了一项为期5年的培训计划，旨在继续发展学术生涯。 肾脏学。首席调查员已在波士顿完成住院医师和临床肾病培训 现在将通过精心制定的计划结合独特的资源来扩大他的科学技能 布里格姆妇女医院和哈佛大学的。 该计划将促进对上皮细胞生物学的指挥，因为它与肾脏损伤和纤维化有关。这个 首席研究员的科学发展将由首席研究员约瑟夫·邦文特尔博士推动 肾内科。为了加强培训，这项提议包括与安德鲁博士合作 麦克马洪说，他是调控生长和分化的细胞和分子机制方面的专家。在……里面 此外，一个咨询委员会将提供科学建议和职业指导。该委员会包括 丹尼斯·布朗博士，肾上皮细胞生物学家和显微镜专家，拉古·卡鲁里博士，细胞外 矩阵生物学家和免疫学家兼小鼠转基因核心设施主任阿琳·夏普博士。 研究的重点将是肾脏损伤分子-1(Kim-1)，这是一种由Dr。 肾损伤后在近端肾小管上皮细胞中强烈诱导的Bonventre实验室。 在体外促进去分化的细胞表型，我们假设Kim-1在小管中辅助 通过促进细胞脱分化和增殖促进损伤后的再生 完整的肾小管上皮。然而，这种蛋白的异常或慢性表达可能会促使上皮细胞 间质转化(EMT)并最终导致肾纤维化。这项建议的具体目的 包括：1)使用细胞培养模型表征依赖于Kim-1 EMT和信号通路；2)识别 使用酵母双杂交技术与Kim-1细胞质结构域相互作用的蛋白质和3) 建立肾近端小管靶向过表达Kim-1的小鼠模型 慢性过表达的Kim-1促进了肾脏纤维化。 在我们老龄化的人口中，慢性肾脏疾病的患病率越来越高，这是一个巨大的 健康负担。因为慢性肾病的最终共同途径是肾脏纤维化，治疗方法 逆转或缓慢的纤维化将产生巨大的临床影响。这些研究可能会证实Kim-1是一种 它是肾脏纤维化的治疗靶点，因此具有极大的公共卫生意义。

This proposal describes a 5 year training program for the continued development of a career in academic nephrology. The principal investigator has completed residency and clinical nephrology training in Boston and now will expand his scientific skills through a carefully formulated plan combining the unique resources of Brigham and Women's Hospital and Harvard University. The plan will promote command of epithelial cell biology as it relates to renal injury and fibrosis. The principal investigator's scientific development will be fostered by Dr. Joseph Bonventre, the Chief of the Division of Nephrology. To enhance training, this proposal includes a collaboration with Dr. Andrew McMahon, an expert in the cellular and molecular mechanisms which regulate growth and differentiation. In addition, an advisory committee will provide scientific advice and career guidance. The committee includes Dr. Dennis Brown, a renal epithelial cell biologist and expert microscopist, Dr. Raghu Kalluri, an extracellular matrix biologist and Dr. Arlene Sharpe, an immunologist and Director of the mouse transgenic core facility. Research will focus on Kidney Injury Molecule-1 (Kim-1), a membrane protein identified by Dr. Bonventre's lab that is strongly induced in proximal tubular renal epithelium after kidney injury.Kim-1 promotes a dedifferentiated cell phenotype in vitro, and we hypothesize that Kim-1aids in tubular regeneration after injury by promoting cellular dedifferentiation and proliferation leading to regeneration of an intact tubular epithelium. Aberrant or chronic expression of this protein, however, may drive epithelial to mesenchymal transition (EMT)and ultimately cause renal fibrosis. The specific aims of this proposal include: 1) Characterize Kim-1 dependent EMT and signaling pathways using cell culture models, 2) Identify proteins that interact with the cytoplasmic domain of Kim-1using the yeast two-hybrid technique and 3) Create a mouse model with targeted overexpression of Kim-1 in renal proximal tubules to determine whether chronic overexpression of Kim-1 promotes renal fibrosis. The increasing prevalence of chronic kidney disease in our aging population represents an enormous health burden. Because the final common pathway for chronic nephropathies is renal fibrosis, therapies that reverse or slow fibrosis would have tremendous clinical impact. These studies could validate Kim-1 as a therapeutic target in renal fibrosis and are therefore of great public health interest.