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PROJECT 2- MOLECULAR & CELLULAR MECHANISMS AAs

项目 2-分子

基本信息

批准号：
8069936
负责人：
SHINYA SHIBUTANI
金额：
$ 43.8万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-05 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069936
关键词：
Affect Animals Aristolochia Aristolochic Acids Attention Biochemical Biochemical Pathway Biochemical Process Carcinogens Cell Culture Techniques Cells Chronic Kidney Failure DNA DNA Adducts DNA Damage Drug Metabolic Detoxication Enzyme Gene Enzymes Epithelial Experimental Models Fibrosis Gene Expression Genes Genetic Polymorphism Human In Vitro Individual Injury Kidney Kidney Diseases Malignant Neoplasms Mediating Mesenchymal Metabolic Metabolism Mitochondria Modeling Molecular Molecular Profiling Mouse Strains Mus Nephrotoxic Organ Pathology Pathway interactions Plant Components Predisposition Principal Investigator Process Proteomics Proximal Kidney Tubules Rattus Reaction Relative (related person)Renal tubule structure Resistance Rodent Role Toxic effect Toxin Tubular formation Urinary tract Urothelial Cell adduct aristolochic acid II carcinogenesis cell injury epithelial to mesenchymal transition genotoxicity in vivo kidney cell mouse model neoplastic programs repaired response

项目摘要

Principal Investigator/Program Director (Last, First, Middle): Grollman, Arthur P DESCRIPTION: PROJECT 2 Aristolochic acid (AA), the principal component of plants belonging to the genus Aristolochiae, is a potent human nephrotoxin and carcinogen. Its toxic effects are targeted primarily to the renal proximal tubule where it causes cellular injury leading to cortical tubulointerstitial fibrosis, and ultimately, chronic renal failure. The pathology of this nephropathy is well defined but little is known about the biochemical mechanisms by which AA exerts its nephrotoxic action or how it promotes organ specific carcinogenesis. We hypothesize that AA and/or one of its metabolites act through two separate and distinct cellular mechanisms; namely, (a) transporter-mediated concentration and metabolism in renal proximal tubule cells, where the toxin induces tubular injury; and (b) by reacting with DMAto form dA- and dG-AA adducts that initiate neoplastic change in urothelial cells. A spectrum of experimental models including whole animal, perfused kidney, isolated renal proximal tubules, and cell culture will be used to identify mechanisms for renal handling of AA and the biochemical pathways used for AA metabolic transformation(s). We will take advantage of naturally occurring mouse strains that are sensitive or resistant to AA toxicity to identify processes associated with relative susceptibility. Isolated perfused rat kidneys, renal proximal tubules isolated from mouse and human kidney, and cell culture models, will be used to examine mechanisms by which AA and its metabolites are transported by, and exert their toxic effects, in the proximal tubule, with a focus on defining the roles of mitochondria and oxidative injury in the nephrotoxic response. Pathways involved in the proximal tubule response to AA in induction of tubulointerstitial fibrosis through epithelial-to-mesenchymal transition, and in the human ureteric urothelial cell response to AA as it relates to DMA damage and carcinogenesis, will be studied by gene array expression profiling and proteomics analysis. The formation and repair of AA-DNA adducts will be explored in vivo with mouse models of AA nephropathy, and in vitro with isolated mouse and human tubules, and human ureteric urothelial cell cultures, with an emphasis on defining mechanisms related to AA nephro- and genotoxicity. Finally, we will identify genes and enzymes involved in activation and detoxification of AA and its metabolites, with the thought that genetic polymorphisms may predispose certain individuals to AA nephropathy and/or urothelial cell cancer by altering the expression or function of these enzymes.

首席研究员/项目主管（最后、第一、中）：Grollman, Arthur P