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

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生性疾病(MPD),其特征是大量症状性全身炎症、血栓栓塞并发症和生存期受损。大多数PV患者在诊断时缺铁,这是加剧了反复治疗性静脉切开术,治疗的支柱。因此,PV患者经常患有缺铁相关症状而没有治疗选择。铁缺乏如何发展在PV患者开始静脉切开术之前是不清楚的,它是否以及如何有助于PV的炎症状态是未探讨的。此外,最近铁代谢研究的复兴和对缺铁性贫血如何发生的更清楚的理解使我们能够提出一个首要问题:缺铁是否在PV患者中观察到的炎症中起因果作用?为了解决这些问题,我们生成了初步数据,表明缺铁 特别是在巨噬细胞内,相对于铁充足的巨噬细胞,诱导炎性细胞因子的产生。因此,我们以前已经表明,铁调素模拟剂螯合铁在PV小鼠脾巨噬细胞。此外,我们现在在我们目前的II期临床试验中使用铁调素模拟物PTG-300证实,巨噬细胞中增加的铁螯合同时能够控制血细胞比容,逆转全身性铁缺乏症,并减少PV患者的炎症相关症状。这些发现提高了PV患者中铁耗尽的巨噬细胞可能对铁调素抑制不充分负责的强烈可能性,并且部分导致不能恢复到稳态铁吸收,证明了铁缺乏诱导负反馈以增加铁调素的新机制。 鉴于巨噬细胞在炎症中的重要作用,我们推测巨噬细胞中的铁缺乏在PV的病理生理学中是至关重要的。为了验证这一假设,我们建议评估铁代谢的标志物,炎症的标志物,和功能终点的PV小鼠脾巨噬细胞铁充足和缺铁饮食,以及与hepcidin模拟物治疗。综上所述,我们预计这些研究将为我们修订后重新提交的R 01申请中提出的研究提供额外的概念和技术支持。

项目成果

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Yelena Ginzburg其他文献

Yelena Ginzburg的其他文献

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{{ truncateString('Yelena Ginzburg', 18)}}的其他基金

Regulatory role of iron transport in stress and ineffective erythropoiesis
铁转运在应激和无效红细胞生成中的调节作用
  • 批准号:
    9312489
  • 财政年份:
    2016
  • 资助金额:
    $ 10万
  • 项目类别:
Regulatory role of iron transport in stress and ineffective erythropoiesis
铁转运在应激和无效红细胞生成中的调节作用
  • 批准号:
    9763567
  • 财政年份:
    2016
  • 资助金额:
    $ 10万
  • 项目类别:
The Role of Erythroferrone in Regulating Bone Metabolism in Beta-Thalassemia
赤铁酮在调节β-地中海贫血骨代谢中的作用
  • 批准号:
    10366984
  • 财政年份:
    2015
  • 资助金额:
    $ 10万
  • 项目类别:
The Role of Erythroferrone in Regulating Bone Metabolism in Beta-Thalassemia
赤铁酮在调节β-地中海贫血骨代谢中的作用
  • 批准号:
    10807992
  • 财政年份:
    2015
  • 资助金额:
    $ 10万
  • 项目类别:
Regulatory role of iron transport in stress and ineffective erythropoiesis
铁转运在应激和无效红细胞生成中的调节作用
  • 批准号:
    9008887
  • 财政年份:
    2015
  • 资助金额:
    $ 10万
  • 项目类别:
The Role of Erythroferrone in Regulating Bone Metabolism in Beta-Thalassemia
赤铁酮在调节β-地中海贫血骨代谢中的作用
  • 批准号:
    10560583
  • 财政年份:
    2015
  • 资助金额:
    $ 10万
  • 项目类别:
Understand and Improve Iron Distribution and Erythropoiesis in Beta-Thalassemia
了解并改善β地中海贫血的铁分布和红细胞生成
  • 批准号:
    8431747
  • 财政年份:
    2011
  • 资助金额:
    $ 10万
  • 项目类别:
Understanding and Improving Iron Distribution and Erythropoiesis in Beta-Thalasse
了解和改善 Beta-Thalasse 中的铁分布和红细胞生成
  • 批准号:
    8030271
  • 财政年份:
    2011
  • 资助金额:
    $ 10万
  • 项目类别:
Understand and Improve Iron Distribution and Erythropoiesis in Beta-Thalassemia
了解并改善β地中海贫血的铁分布和红细胞生成
  • 批准号:
    8228015
  • 财政年份:
    2011
  • 资助金额:
    $ 10万
  • 项目类别:

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