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Targeting Ferritin in Vascular Calcification Associated With CKD

靶向 CKD 相关血管钙化中的铁蛋白

基本信息

批准号：
10307541
负责人：
Abolfazl Zarjou
金额：
$ 16.83万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307541
关键词：
Ablation Alkaline Phosphatase Anemia Arterial Fatty Streak Attenuated Award Bioinformatics Biology Biometry Blood Vessels Cardiovascular system Cell Compartmentation Cell physiology Cells Ceruloplasmin Chemopreventive Agent Chemoprotective Agent Chronic Kidney Failure Clinical Complication Consequentialism Data Analyses Development Diet Doctor of Philosophy Down-Regulation Educational Curriculum End stage renal failure Environment Etiology Event Excretory function Fellowship Ferritin Functional disorder Gene Expression Profiling Genes Goals Health Heme Iron Hungary Hydroxyapatites In Vitro Investigation Ions Iron Iron deficiency anemia Kidney Kidney Diseases Kidney Failure Knowledge Laboratories Light Medial Mediating Medical Students Mentors Mentorship Modeling Molecular Morbidity - disease rate Mus Osteoblasts Osteocalcin Pathologic Pathway interactions Patient-Focused Outcomes Patients Phosphorus Physicians Prevention Preventive Process Prognostic Marker Property Proteins Renal dialysis Reporting Research Research Personnel Research Training Residencies Risk Risk Factors Role Scientist Smooth Muscle Myocytes Stimulant Techniques Testing Therapeutic Thiones Training Transgenic Mice Up-Regulation Vascular Smooth Muscle Vascular calcification Work base blood treatment calcification career career development core binding factor alpha coronary artery calcification design experience improved in vivo indexing inorganic phosphate insight interest iron deficiency iron metabolism knowledge base mineralization mortality mouse model novel novel strategies novel therapeutic intervention novel therapeutics osteoblast differentiation overexpression oxidative damage peer coaching prevent programs protective effect skills transcription factor transcriptome transcriptome sequencing

项目摘要

Abstract The foremost objective of my career is to become an independent and successful physician-scientist in the field of cardiovascular complications of chronic kidney disease (CKD). My passion to achieve this objective has helped me since my training began as a medical student in Hungary. To enrich my experience, knowledge and skills I pursued a PhD degree and worked relentlessly to establish the beginning of my career in U.S. Continuing on the same path, I was selected in the ABIM research pathway at UAB, a competitive combined program for residency, fellowship and research training. To fully achieve the goals of my career with an overall emphasis on improving the health of patients with kidney diseases, I will need further training and mentorship that will also serve as a fundamental requisite for successful completion of the following scientific premise: Calcification of the vasculature is commonly found in patients with advanced CKD and is associated with increased morbidity and mortality. There is hence an urgent unmet need to find answers to etiologic and mechanistic questions in order to introduce novel therapeutics. Advanced CKD often results in phosphate retention and iron deficiency anemia. Whether such iron deficiency in advanced CKD patients promotes vascular calcification has not been elucidated. We previously reported that iron and 3H-1,2-Dithiole-3-thione (D3T) induced expression of intracellular ferritin heavy chain (FtH) mitigates transformation of vascular smooth muscle cells into osteoblast like cells. Based on our preliminary findings, we hypothesize that derangements in iron metabolism with subsequent decrements in intracellular FtH expression, accelerate CKD associated vascular calcification. In support of this concept, we hypothesize that parenteral iron administration may be considered to correct anemia and to prevent vascular calcification in CKD patients. We will also examine the exciting potential of D3T (a chemo-preventive agent and FtH stimulant), as a therapeutic/preventive agent against vascular calcification. In this study, we will utilize novel transgenic mice with conditional deletion of FtH in the vascular smooth muscle cell compartment to test this hypothesis in a model of CKD and hyperphosphatemia. Additionally, to fully understand the inhibitory role of FtH, we will utilize an unbiased analysis of gene expression using RNA seq and examine pathways that are involved in the vascular protective effects of FtH. Of equal importance, this proposal will serve as a comprehensive strategy intended to transition me from trainee to independent investigator. I present a curriculum designed to enhance 1) knowledge base in vascular biology, bioinformatics and biostatistics, 2) technical repertoire with a focus on translational techniques, 3) professional development through peer mentoring and gaining skills in laboratory management. This training will be under the guidance of accomplished and respected mentors in a high quality environment for scientific discovery and career development. I plan to take full advantage of this training award with the overall objective of providing meaningful contributions to improve health and outcomes of patients with CKD.

抽象的我职业生涯的首要目标是成为该领域独立且成功的医师科学家慢性肾脏病（CKD）的心血管并发症。我对实现这一目标的热情自从我在匈牙利作为一名医科学生接受培训以来，这对我很有帮助。丰富我的经验、知识和我攻读了博士学位，并坚持不懈地努力，在美国开启了我的职业生涯继续在同样的道路上，我被选入 UAB 的 ABIM 研究途径，这是一个竞争性的综合项目住院医师、研究员和研究培训。全面实现我的职业目标，重点是改善肾脏疾病患者的健康，我需要进一步的培训和指导，这也将作为成功完成以下科学前提的基本前提：血管钙化常见于晚期 CKD 患者，并且与发病率和死亡率增加。因此，迫切需要找到病因和问题的答案，但尚未得到满足。机制问题以引入新的疗法。晚期 CKD 通常会导致磷酸盐潴留和缺铁性贫血。晚期 CKD 患者缺铁是否会促进血管生成钙化尚未阐明。我们之前报道过铁和 3H-1,2-二硫醇-3-硫酮 (D3T) 细胞内铁蛋白重链 (FtH) 的诱导表达可减轻血管平滑肌的转化细胞转变为成骨细胞样细胞。根据我们的初步发现，我们假设铁的紊乱代谢以及随后细胞内 FtH 表达的减少，加速 CKD 相关血管的发生钙化。为了支持这一概念，我们假设可以考虑肠外铁剂给药纠正贫血并预防 CKD 患者的血管钙化。我们还将研究令人兴奋的潜力 D3T（化学预防剂和 FtH 兴奋剂）作为血管性治疗/预防剂钙化。在这项研究中，我们将利用血管内条件性删除 FtH 的新型转基因小鼠。平滑肌细胞区室在 CKD 和高磷血症模型中检验这一假设。此外，为了充分了解 FtH 的抑制作用，我们将利用 RNA 对基因表达进行无偏分析 seq 并检查参与 FtH 血管保护作用的途径。同样重要的是，该提案将作为一项全面战略，旨在帮助我从独立调查员的实习生。我提出的课程旨在增强 1) 血管知识基础生物学、生物信息学和生物统计学，2) 重点关注转化技术的技术库，3) 通过同行指导和获得实验室管理技能进行专业发展。此次培训将在高质量的科学环境中接受有成就和受人尊敬的导师的指导发现和职业发展。我计划充分利用这次培训奖的总体目标为改善 CKD 患者的健康和预后做出有意义的贡献。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Heme Burden and Ensuing Mechanisms That Protect the Kidney: Insights from Bench and Bedside.

DOI：
10.3390/ijms22158174
发表时间：
2021-07-30
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Balla J;Zarjou A
通讯作者：
Zarjou A

Lactated Ringer's solution and risk of hyperkalemia in patients with reduced kidney function.

乳酸林格氏液和肾功能下降患者高钾血症的风险。

DOI：
10.1016/j.amjms.2022.04.024
发表时间：
2022-10
期刊：
AMERICAN JOURNAL OF THE MEDICAL SCIENCES
影响因子：
3.1
作者：
Rajasekaran, Arun;Bade, Naveen;Cutter, Gary R.;V. Rizk, Dana;Zarjou, Abolfazl
通讯作者：
Zarjou, Abolfazl

A Reproducible Mouse Model of Moderate CKD With Early Manifestations of Osteoblastic Transition of Cardiovascular System.