Mechanistic understanding of dysregulated iron metabolism in polycythemia vera

项目摘要/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)，其特征是明显的症状性全身炎症、血栓栓塞性并发症和预后不良。大多数PV患者在确诊时都是缺铁的，而反复的治疗性静脉抽吸术是治疗的主要手段，从而加剧了这种情况。因此，PV患者经常出现与缺铁相关的症状，没有治疗选择。静脉曲张患者在开始放血前铁缺乏是如何发生的还不清楚，也不清楚它是否以及如何导致皮肤病的炎症状态。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患者观察到的炎症中起因果作用？为了解决这些问题，我们产生了初步数据，表明缺铁 具体地说，在巨噬细胞内，诱导产生与铁充足的巨噬细胞相关的炎性细胞因子。我们之前一直证明，在PV小鼠的脾巨噬细胞中，海普西丁的模拟剂将铁隔离。此外，我们现在使用海普西丁模拟PTG-300在我们目前的II期临床试验中证实，增加巨噬细胞中的铁隔离同时能够控制红细胞压积，逆转全身性铁缺乏，并减少PV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PV患者中铁耗竭的巨噬细胞可能是未充分抑制海普西丁的原因，部分原因是无法恢复到稳定的铁吸收，这表明了一种新的机制，即缺铁导致负反馈增加海普西丁。 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PV的病理生理学中起关键作用。为了验证这一假设，我们建议评估铁充足和铁缺乏饮食以及海普西丁类似物治疗的PV小鼠脾巨噬细胞中铁代谢标志、炎症标志和功能终点。综上所述，我们预计这些研究将为我们重新提交的修订后的R01申请中提议的研究提供额外的概念和技术支持。

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.