Mechanistic understanding of dysregulated iron metabolism in polycythemia vera

真性红细胞增多症铁代谢失调的机制理解

基本信息

批准号：
10681065
负责人：
Yelena Ginzburg
金额：
$ 10万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10681065
关键词：
Address Affect Agonist Anemia Biology Cell model Cells Characteristics Chronic Complex Data Development Diagnosis Diet Dietary Iron Elements Erythroblasts Erythroid Erythropoiesis Erythropoietin Receptor Evolution Exhibits Exons Fatigue Feedback Functional disorder Future Generations Hematocrit procedure Hematological Disease Hematology Hematopoietic Hemorrhagic Thrombocythemia Hormones Human Hypersensitivity Impaired cognition Impairment In Transferrin In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Iron JAK2 gene Light Mediating Megakaryocytes Molecular Mus Mutation Myelofibrosis Myeloproliferative disease Organ Patients Phase II Clinical Trials Phenotype Physiology Play Polycythemia Vera Primary Myelofibrosis Production Proliferating Receptor Signaling Regulation Renaissance Reporting Research Role Signal Transduction Splenomegaly Symptoms Testing Therapeutic Therapeutic Agents Time Venous blood sampling alpha-Thalassemia associated symptom base cell type cytokine hepcidin in vivo inflammatory marker inflammatory milieu insight iron absorption iron deficiency iron metabolism macrophage mimetics monocyte mouse model novel progenitor public health relevance response systemic inflammatory response thrombotic complications transferrin receptor 2

项目摘要

Project Summary/abstract Polycythemia vera (PV) is a clonal hematologic myeloproliferative disorder (MPD) characterized by substantial symptomatic systemic inflammation, thromboembolic complications, and impaired survival. Most patients with PV are iron deficient at diagnosis, which is exacerbated by repeated therapeutic phlebotomies, the mainstay of treatment. As a result, PV patients often suffer from iron deficiency related symptoms without treatment options. How iron deficiency develops in PV patients prior to the initiation of phlebotomy is not well understood and whether and how it contributes to the inflammatory state in PV is unexplored. Furthermore, a recent renaissance in iron metabolism research and a more clear understanding of how anemia occurs in iron deficiency has enabled us to ask an overarching question: does iron deficiency play a causal role in the inflammation observed in PV patients? To address these questions, we generated preliminary data demonstrating that iron deficiency specifically within macrophages induces the production of inflammatory cytokines relative to iron replete macrophages. Consistently, we have previously shown that hepcidin-mimetic agents sequester iron in splenic macrophages in PV mice. Furthermore, we now confirm in our current phase II clinical trial using hepcidin mimetic PTG-300 that increased iron sequestration in macrophages simultaneously enables hematocrit control, reverses systemic iron deficiency, and reduces inflammation-associated symptoms in PV patients. These findings raise the strong possibility that iron depleted macrophages in PV patients may be responsible for the insufficiently suppressed hepcidin and in part result in the inability of return to steady state iron absorption, demonstrating a novel mechanism by which iron deficiency induces a negative feedback to increase hepcidin. In light of the important role of macrophages in inflammation, we hypothesize that iron deficiency specifically in macrophages is critical in the pathophysiology of PV. To test this hypothesis, we propose to evaluate markers of iron metabolism, markers of inflammation, and functional endpoints in splenic macrophage from PV mice on iron replete and iron deficient diet as well as treated with hepcidin-mimetics. Taken together, we anticipate that these studies will provide additional conceptual and technical support for the studies proposed in our revised resubmitted R01 application.

项目概要/摘要真性红细胞增多症 (PV) 是一种克隆性血液学骨髓增殖性疾病 (MPD)，其特征是明显的症状性全身炎症、血栓栓塞并发症和生存受损。大多数真性红细胞增多症患者在诊断时就缺铁，反复进行静脉放血治疗（主要治疗方法）会加剧缺铁情况。因此，真性红斑狼疮患者经常出现缺铁相关症状，而没有治疗选择。在开始放血之前，PV 患者缺铁是如何发生的尚不清楚，铁缺乏是否以及如何导致 PV 炎症状态也尚未被探索。此外，最近铁代谢研究的复兴以及对缺铁性贫血如何发生的更清晰的了解使我们能够提出一个首要问题：铁缺乏是否在真性红斑狼疮患者观察到的炎症中起着因果作用？为了解决这些问题，我们生成了初步数据，证明缺铁特别是在巨噬细胞内，相对于铁充足的巨噬细胞，诱导炎症细胞因子的产生。一致地，我们之前已经证明铁调素模拟剂在 PV 小鼠的脾巨噬细胞中螯合铁。此外，我们现在在当前的 II 期临床试验中证实，使用铁调素模拟物 PTG-300 增加巨噬细胞中的铁固存，同时能够控制血细胞比容，逆转全身性缺铁，并减少真性红斑狼疮患者的炎症相关症状。这些发现提出了一种很强的可能性，即真性红斑狼疮患者中缺铁的巨噬细胞可能是铁调素抑制不充分的原因，并在一定程度上导致铁吸收无法恢复到稳态，这证明了铁缺乏导致负反馈增加的新机制。铁调素。鉴于巨噬细胞在炎症中的重要作用，我们假设巨噬细胞中的铁缺乏在真性红斑狼疮的病理生理学中至关重要。为了检验这一假设，我们建议评估铁代谢标志物、炎症标志物以及接受铁充足和缺铁饮食以及铁调素模拟物治疗的 PV 小鼠脾巨噬细胞的功能终点。总而言之，我们预计这些研究将为我们修订后重新提交的 R01 申请中提出的研究提供额外的概念和技术支持。