Iron and renal fibrosis in juvenile chronic kidney disease

青少年慢性肾病中的铁和肾纤维化

• 批准号: 10224883
• 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
• 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/10224883
• 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

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 这是一个K 08指导临床科学家研究职业发展奖博士的申请。 Oleh Akchurin是纽约州纽约威尔康奈尔医学院的儿科肾病学家。阿克丘林博士是 在儿科慢性肾脏病领域成为一名年轻的研究者和转化研究者 病（CKD）。该奖项将为他提供必要的支持，以实现以下目标：（1） 成为青少年CKD转化研究的专家，重点关注铁代谢的改变;（2） 进行铁剂治疗青少年CKD肾性贫血对肾性贫血的影响的实验研究， 纤维化，如自噬的变化所介导的;（3）在这些疾病中实施先进的实验室技术， 研究;（4）提高解释和分析科学数据的技能;（5）发展独立的 研究生涯。为了实现这些目标，Akchurin博士组建了一个由有成就的研究人员组成的团队： 主要导师玛丽博士E. Choi博士是一位肾脏病学家，擅长肾纤维化和自噬; Stefano Rivella，铁代谢专家;和顾问Surya Seshan博士，世界著名的肾脏病专家， 病理学家，以及铁依赖性自噬和程序性细胞死亡途径专家Xuejun Jiang博士， 以及他的顾问委员会成员。 虽然铁治疗在CKD儿童中非常常见，但铁的有害作用一直存在。 在急性肾损伤中，铁代谢改变和铁剂治疗在肾纤维化中的作用是明确的， 青少年CKD的范围仍然未知。同样，虽然我们知道铁的促氧化活性 潜在的破坏细胞内大分子，需要通过自噬回收，铁的作用 在调节肾纤维化中促存活自噬活性方面还没有研究。最近的研究博士。 Akchurin强烈支持这一假设，即口服铁在目前的治疗水平，导致肾铁 在青少年CKD中，自噬的累积和加重肾纤维化，部分由改变的肾自噬介导。 在此期间获奖，他将测试这一假设使用腺嘌呤为基础的小鼠模型的少年 CKD。此外，Akchurin博士还将研究他的发现的机制，特别是针对 自噬在铁介导的肾纤维化加重中的作用，如他的初步研究中所确定的。本研究 将为确定铁对肾功能影响的相关分子机制奠定基础。 在青少年CKD纤维化，并告知新的治疗目标，这将在R 01赠款申请中提出 在K 08奖结束之前。