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Iron and renal fibrosis in juvenile chronic kidney disease

青少年慢性肾病中的铁和肾纤维化

基本信息

批准号：
10458519
负责人：
Oleh Akchurin
金额：
$ 16.63万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458519
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Adenine Adolescent Adult Advisory Committees Affect Anemia Animals Apoptosis Applications Grants Autophagocytosis Autophagosome Award Cells Child Childhood Chronic Kidney Failure Clinical Data Development Dialysis procedure Diet Disease Progression End stage renal failure Erythropoietin Evaluation Fibrosis Functional disorder Gene Proteins Goals Growth Hemoglobin Histology Hormones Human Impairment Incidence Inflammation Injury Investigation Iron Iron Overload K-Series Research Career Programs Kidney Knock-out Knowledge Laboratories Leupeptins Mediating Mentors Molecular Mus New York Oral Oxidative Stress Pathologist Pathway interactions Patients Prevalence Process Reactive Oxygen Species Regulation Renal function Reporting Research Research Personnel Role Scientist Serum Techniques Testing Therapeutic Time Tissues Training Translating Translational Research Uremia Wild Type Mouse animal data base career hepcidin improved iron metabolism iron supplementation kidney dysfunction kidney fibrosis knockout gene macromolecule medical schools member mouse model mutant new therapeutic target prevent protective effect skills translational scientist

项目摘要

ABSTRACT This is an application for a K08 Mentored Clinical Scientist Research Career Development Award for Dr. Oleh Akchurin, a pediatric nephrologist at Weill Cornell Medical College, New York, NY. Dr. Akchurin is establishing himself as a young investigator and translational researcher in the field of pediatric chronic kidney disease (CKD). This award will provide him with the support necessary to accomplish the following goals: (1) to become an expert in translational research of juvenile CKD, with a focus on altered iron metabolism; (2) to conduct experimental investigations of the effects of iron therapy for renal anemia in juvenile CKD on renal fibrosis, as mediated by changes in autophagy; (3) to implement advanced laboratory techniques in these studies; (4) to advance skills in interpreting and analyzing scientific data; and (5) to develop an independent research career. To achieve these goals, Dr. Akchurin has assembled a team of accomplished investigators: his primary mentor Dr. Mary E. Choi, a nephrologist with expertise in renal fibrosis and autophagy; co-mentor Dr. Stefano Rivella, an expert in iron metabolism; and consultants Dr. Surya Seshan, a world-renowned renal pathologist, and Dr. Xuejun Jiang, an expert in iron-dependent autophagy and programmed cell death pathways, as well as members of his Advisory Committee. Although iron therapy is very common in children with CKD and the detrimental action of iron has been well established in acute kidney injury, the role of altered iron metabolism and iron therapy in renal fibrosis in the sphere of juvenile CKD remains unknown. Similarly, while we understand that iron's pro-oxidative activity has the potential to damage intracellular macromolecules which need to be recycled by autophagy, the role of iron in modulating pro-survival autophagic activity in renal fibrosis has not been examined. Recent studies by Dr. Akchurin strongly support the hypothesis that oral iron given at current therapeutic levels causes kidney iron accumulation and exacerbates renal fibrosis in juvenile CKD, as mediated in part by altered renal autophagy. During the period of this award, he will test this hypothesis using an adenine-based mouse model of juvenile CKD. In addition, Dr. Akchurin will investigate the mechanism of his findings, specifically targeting the role of autophagy in iron-mediated aggravation of renal fibrosis, as identified in his preliminary studies. This research will form the basis for identification of relevant molecular mechanisms underlying the impact of iron on renal fibrosis in juvenile CKD, and inform novel therapeutic targets, which will be proposed in an R01 grant application before the end of the K08 award.

摘要