Targeting Ferritin in Vascular Calcification Associated With CKD

摘要 我的职业生涯的首要目标是成为一个独立的和成功的物理科学家在该领域 慢性肾脏病（CKD）的心血管并发症。我对实现这一目标的热情 从我在匈牙利接受医学训练开始就一直在帮助我。为了丰富我的经验，知识和 技能我追求博士学位，并不懈地工作，以建立我的职业生涯在美国的开始。 在同一条道路上，我被选为UAB的ABIM研究途径，这是一个竞争性的综合项目， 居住、研究金和研究培训。为了充分实现我的职业目标，我的总体重点是 为了改善肾病患者的健康，我需要进一步的培训和指导， 作为成功完成以下科学前提的基本必要条件： 血管钙化常见于晚期CKD患者， 发病率和死亡率增加。因此，迫切需要找到病因学的答案， 机械问题，以引入新的治疗方法。晚期CKD通常会导致磷酸盐 和缺铁性贫血。晚期CKD患者的铁缺乏是否会促进血管 钙化尚未阐明。我们以前报道过铁和3H-1，2-二硫杂环戊烯-3-酮（D3T） 诱导表达细胞内铁蛋白重链（FtH）减轻血管平滑肌转化 成骨细胞样细胞。基于我们的初步发现，我们假设铁的紊乱 随着细胞内FtH表达的减少，CKD相关的血管代谢加速， 钙化为了支持这一概念，我们假设，肠外铁剂给药可能被认为是 纠正CKD患者的贫血和预防血管钙化。我们还将研究令人兴奋的潜力 D3T（一种化学预防剂和FtH兴奋剂），作为血管性疾病的治疗/预防剂， 钙化在这项研究中，我们将利用新的转基因小鼠与条件删除FtH的血管， 平滑肌细胞隔室，以在CKD和高磷酸盐血症模型中检验这一假设。此外，本发明还 为了充分理解FtH的抑制作用，我们将利用RNA技术对基因表达进行无偏分析， seq和检查参与FtH血管保护作用的途径。 同样重要的是，这项建议将作为一项全面战略， 从实习生到独立调查员我提出了一个课程，旨在提高1）知识基础，血管 生物学、生物信息学和生物统计学，2）侧重于翻译技术的技术库，3） 通过同伴指导和获得实验室管理技能来实现专业发展。本次培训将 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培训奖的总体目标 为改善CKD患者的健康和结局做出有意义的贡献。

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.