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.

抽象的 这是博士博士的K08指导临床科学家研究职业发展奖的申请。 Oleh Akchurin，纽约Weill Cornell医学院的儿科肾脏科医生。 Akchurin博士是 在小儿慢性肾脏领域建立自己的年轻研究员和翻译研究员 疾病（CKD）。该奖项将为他提供实现以下目标所需的支持：（1） 成为少年CKD转化研究的专家，重点是改变铁代谢； （2）至 对铁治疗对幼年CKD肾脏贫血的影响进行实验研究 纤维化，由自噬的变化介导； （3）在这些中实施高级实验室技术 研究； （4）提高解释和分析科学数据的技能； （5）建立独立 研究职业。为了实现这些目标，Akchurin博士组建了一支成熟的调查员团队：他的 主要导师玛丽·乔（Mary E.联合主管博士 铁代谢专家Stefano Rivella；和顾问Surya Seshan博士，世界知名的肾脏 病理学家和依赖铁的自噬和程序性细胞死亡途径专家Xuejun Jiang博士， 以及他的咨询委员会成员。 尽管铁治疗在CKD儿童中非常普遍，铁的有害作用一直很常见 在急性肾脏损伤中建立了良好的，铁代谢改变和铁治疗在肾纤维化中的作用 少年CKD领域仍然未知。同样，尽管我们了解铁的促氧化活性具有 损害需要通过自噬来回收的细胞内大分子的潜力，铁的作用 在调节肾纤维化中的促生存自噬活性时，尚未检查。博士的最新研究 Akchurin强烈支持以下假设：在当前治疗水平下给出的口服铁会导致肾铁 幼年CKD中的肾纤维化的积累并加剧，部分是由于肾脏自噬改变的部分介导的。 在此奖项期间，他将使用基于腺嘌呤的幼体模型检验该假设 CKD。此外，Akchurin博士将研究其发现的机制，特别针对 在他的初步研究中确定的铁介导的肾纤维化加剧中自噬。这项研究 将构成鉴定铁对肾脏影响的相关分子机制的基础 少年CKD中的纤维化，并为新颖的治疗靶标提供信息，该靶标将在R01赠款应用中提出 在颁发K08奖之前。