Iron and renal fibrosis in juvenile chronic kidney disease

摘要 这是一份K08临床科学家导师研究职业发展奖的申请表。 纽约威尔·康奈尔医学院的儿科肾病学家奥莱·阿克霍林说。阿克霍林博士 在儿科慢性肾脏领域确立自己作为年轻研究员和翻译研究员的地位 疾病(CKD)。这一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翻译研究的专家，专注于铁代谢改变；(2) 铁剂治疗幼年型CKD肾性贫血对肾脏影响的实验研究 由自噬变化介导的纤维化；(3)在这些领域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；以及(5)发展独立的 研究生涯。为了实现这些目标，阿克霍林博士组建了一支有成就的研究团队：他的 首席导师玛丽·E·崔博士是一位在肾脏纤维化和自噬方面具有专业知识的肾病学家； 铁代谢专家Stefano Rivella和世界知名肾脏专家Surya Seshan博士 病理学家蒋学军博士是铁依赖自噬和程序化细胞死亡途径方面的专家， 以及他的咨询委员会成员。 虽然铁疗法在慢性肾脏病儿童中非常常见，但铁的有害作用一直是 在急性肾损伤中，铁代谢改变和铁治疗在肾纤维化中的作用已得到证实 幼年型CKD的范围尚不清楚。同样，虽然我们了解铁的促氧化活性具有 对需要通过自噬循环的细胞内大分子的潜在损害，铁的作用 在调节有利于生存的过程中，肾纤维化中的自噬活性尚未得到检验。最近的研究由Dr。 阿克霍林强烈支持这一假说，即在目前的治疗水平下口服铁会导致肾铁。 在幼年型慢性肾脏病中积聚和加剧肾脏纤维化，部分是通过改变肾脏自噬来调节的。 在获奖期间，他将使用以腺嘌呤为基础的幼年小鼠模型来检验这一假说。 CKD。此外，阿克霍林博士将研究他的发现的机制，特别是针对 铁介导的肾纤维化加重中的自噬，如他的初步研究中所确认的。这项研究 将成为确定铁对肾脏影响的相关分子机制的基础 幼年型CKD的纤维化，并提供新的治疗靶点，将在R01拨款申请中提出 在K08大奖结束之前。

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.