Kidney Injury Molecule-1 in Renal Fibrosis

肾纤维化中的肾损伤分子 1

• 批准号: 7754664
• 负责人: BENJAMIN D. HUMPHREYS
• 金额: $ 13.33万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-09 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7754664
• 关键词: Adenoviruses; Advisory Committees; Alkaline Phosphatase; Animals; Apical; Binding; Biological Models; Boston; Cell Culture Techniques; Cell Line; Cell Lineage; Cell Proliferation; Cells; Cellular biology; Chronic; Chronic Kidney Failure; Clinical; Co-Immunoprecipitations; Collaborations; Core Facility; Cytoplasmic Tail; Development; Differentiation and Growth; Epithelial; Epithelial Cells; Epithelium; Event; Extracellular Matrix; Fibrosis; Fostering; Genetic; Health; Hospitals; Immunologist; In Vitro; Infection; Injury; Integral Membrane Protein; Kidney; Kidney Diseases; Laboratories; MDCK cell; Measurement; Mediating; Membrane Proteins; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Myofibroblast; Natural regeneration; Nephrology; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation; Physiological; Plasmid Cloning Vector; Prevalence; Principal Investigator; Proteins; Proximal Kidney Tubules; Public Health; Renal tubule structure; Reporter; Research; Research Personnel; Residencies; Resources; Role; Screening procedure; Signal Pathway; Signal Transduction; Snails; Stimulus; Surface; Techniques; Technology; Tetracyclines; Tight Junctions; Training; Training Programs; Transcriptional Activation; Transferase; Transgenic Mice; Tubular formation; Tyrosine; Universities; Woman; Yeasts; aging population; career; epithelial to mesenchymal transition; improved; in vivo; in vivo Model; interest; interstitial; mouse model; mutant; overexpression; programs; promoter; protein expression; protein protein interaction; rat KIM-1 protein; renal epithelium; repaired; response to injury; rho; skills; therapeutic target; yeast two hybrid system

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.

该提案描述了一项为期5年的培训计划，旨在持续发展学术事业 肾脏学主要研究者已在波士顿完成住院医师和临床肾脏病学培训 现在，他将通过精心制定的计划，结合独特的资源， 布里格姆妇女医院和哈佛大学。 该计划将促进上皮细胞生物学的掌握，因为它与肾损伤和纤维化有关。的 首席研究员的科学发展将由约瑟夫·邦文特博士， 肾脏科。为了加强培训，这项建议包括与安德鲁博士合作， 麦克马洪是调节生长和分化的细胞和分子机制方面的专家。在 此外，一个咨询委员会将提供科学咨询和职业指导。该委员会包括 博士丹尼斯·布朗，肾上皮细胞生物学家和显微镜专家，Raghu Kaghui博士，细胞外 矩阵生物学家和阿琳夏普博士，免疫学家和小鼠转基因核心设施的主任。 研究将集中在肾损伤分子-1（Kim-1）上，这是一种由Dr. Bonventre的实验室，在肾损伤后近端肾小管上皮细胞中强烈诱导。Kim-1 在体外促进去分化细胞表型，我们假设Kim-1aids在肾小管上皮细胞中表达， 通过促进细胞的去分化和增殖，导致细胞的再生， 完整肾小管上皮然而，这种蛋白质的异常或慢性表达可能会驱使上皮细胞 间质转化（EMT）并最终导致肾纤维化。本提案的具体目标 包括：1）使用细胞培养模型表征Kim-1依赖性EMT和信号传导途径，2）鉴定 使用酵母双杂交技术与Kim-1的胞质结构域相互作用的蛋白质; 3） 建立Kim-1在肾近端小管中靶向过表达的小鼠模型，以确定是否 Kim-1的慢性过表达促进肾纤维化。 慢性肾脏疾病在我们老龄化人口中的患病率不断增加， 健康负担。由于慢性肾病的最终共同途径是肾纤维化， 逆转或减缓纤维化将具有巨大的临床影响。这些研究可以验证Kim-1作为 因此，它们是肾纤维化中的治疗靶点，并因此具有很大的公共健康兴趣。