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：
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
项目类别：
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

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最重要目标是成为该领域的独立和成功的医师科学家慢性肾脏疾病（CKD）的心血管并发症。我对实现这一目标的热情自从我的培训开始时就帮助了我。丰富我的经验，知识和我攻读博士学位的技能，并不懈地努力建立我在美国继续的职业生涯的开始在同一条路上，我在UAB的ABIM研究途径中被选中，UAB是一个竞争性合并计划居住，奖学金和研究培训。完全强调我职业生涯的目标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必要条件：脉管系统的钙化通常在晚期CKD患者中发现，并且与发病率和死亡率增加。因此，紧急未满足的需要寻找病因的答案和机械性问题是为了引入新颖的治疗学。高级CKD通常会导致磷酸盐保留和铁缺乏贫血。高级CKD患者的这种铁缺乏症是否促进血管钙化尚未阐明。我们先前报道了铁和3H-1,2-二二二硫代thione（D3T）细胞内铁蛋白重链（FTH）的诱导表达减轻了血管平滑肌的转化细胞进入成骨细胞。根据我们的初步发现，我们假设铁发生了新陈代谢，随后细胞内FTH表达降低，加速CKD相关的血管钙化。为了支持这个概念纠正贫血并预防CKD患者的血管钙化。我们还将研究令人兴奋的潜力 D3T（一种化学预防剂和FTH刺激剂），作为针对血管的治疗/预防剂钙化。在这项研究中，我们将利用血管中有条件缺失的新型转基因小鼠平滑肌细胞室以在CKD和高磷酸血症模型中检验该假设。此外，为了充分了解FTH的抑制作用，我们将使用RNA对基因表达进行公正的分析 SEQ并检查FTH血管保护作用涉及的途径。同样重要的是，该提案将成为旨在将我从学员到独立调查员。我提出了一个旨在增强的课程1）血管中的知识基础生物学，生物信息学和生物统计学，2）专注于翻译技术的技术曲目，3）通过同行指导和获得实验室管理技能的专业发展。这个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与职业发展。我计划充分利用该培训奖，并以整体目标为改善CKD患者的健康和结果提供有意义的贡献。