Targeting Ferritin in Vascular Calcification Associated With CKD

靶向 CKD 相关血管钙化中的铁蛋白

• 批准号: 10063542
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063542
• 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; 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

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.

摘要 我职业生涯的首要目标是成为一名在该领域独立的、成功的内科科学家 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医科学生开始训练以来，我就一直在帮助我。丰富我的经验、知识和 技能我攻读了博士学位，并坚持不懈地工作，为我在美国的职业生涯奠定了基础 在同样的道路上，我被选入了UAB的ABIM研究途径，这是一个竞争激烈的综合项目 住院医师、奖学金和研究培训。为了全面实现我的职业生涯目标，总体上强调 为了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 作为成功完成下列科学前提的基本必要条件： 血管钙化常见于晚期慢性肾脏病患者，并与 发病率和死亡率增加。因此，有一种迫切的未得到满足的需求，即寻找病因和 为了引入新的治疗方法而提出的机械性问题。晚期慢性肾脏病通常导致磷酸盐 滞留和缺铁性贫血。晚期CKD患者的这种铁缺乏是否促进血管 钙化作用尚未阐明。我们以前报道过铁和~3H-1，2-二硫醇-3-硫酮(D3T) 诱导细胞内铁蛋白重链(FTH)表达减轻血管平滑肌转化 细胞分化为成骨细胞样细胞。根据我们的初步发现，我们假设铁中的无序排列 代谢伴随细胞内FTH表达的降低，加速了CKD相关血管的形成 钙化。为了支持这一概念，我们假设肠外补铁可被认为是 纠正CKD患者的贫血和防止血管钙化。我们还将研究令人兴奋的潜力 D3T(一种化学预防药物和FTH刺激剂)，作为血管的治疗/预防药物 钙化。在这项研究中，我们将利用血管中有条件缺失FTH的新型转基因小鼠 在慢性肾脏病和高磷血症模型中验证这一假说。另外， 为了充分了解FTH的抑制作用，我们将使用RNA对基因表达进行无偏见的分析 SEQ和检查与FTH的血管保护作用有关的途径。 同样重要的是，这项提议将作为一项全面战略，旨在使我从 从实习生到独立调查员。我提出了一门课程，旨在增强血管方面的知识基础 生物学、生物信息学和生物统计学，2)以翻译技术为重点的技术曲目，3) 通过同行指导和获得实验室管理技能来实现专业发展。这次培训将 在高质量的科学环境中，在有成就和受人尊敬的导师的指导下 发现和职业发展。我计划充分利用这个训练奖，总体目标是 为改善慢性肾脏病患者的健康和预后作出有意义的贡献。