Iron Deficiency: Molecular and Cellular Consequences

描述(申请人提供)：铁缺乏症是世界上最常见的人类营养缺乏症之一，但在其对器官生理学的影响方面仍具有令人惊讶的糟糕特征。这种疾病最显著的临床后果之一是，即使在血清促红细胞生成素水平较高的情况下，骨髓红细胞的生成也会受到选择性抑制。由此导致的血液异常包括孤立的贫血，白细胞和血小板水平较低。缺铁导致的红系抑制提供了一种抗流变反应，允许根据可获得的铁储备来调整铁的利用。由于几个原因，对潜在途径的进一步了解具有临床意义。首先，这一途径也会导致除缺铁以外的贫血，如与慢性炎症、癌症和肾脏疾病相关的贫血，这些疾病的特点是铁缺陷从储藏室转移到红细胞室。其次，这一途径被有目的地用来限制真性红细胞增多症的肿瘤增殖，其中铁缺乏的治疗诱导抑制了红细胞室的克隆性扩张。第三，超越这一调节机制的潜在治疗或条件可能会加速严重缺铁患者的临床恶化。利用一种新的原代人类造血培养模型系统，并定义了转铁蛋白饱和水平，已经确定了这一途径中的关键信号靶点。特别是，临床上相关的缺铁水平选择性地使一类特定酶的信号活性失活，即以红系特有的方式。这种作用是通过这些酶中特定的修复基团的功能失活而发生的，而不是通过减少蛋白质的表达。逆转录病毒基因筛查发现了一种特定的因子，该因子作用于这些酶的上游，使红系祖细胞完全抵抗生理性缺铁的影响。已经确定了一种作用于这些酶下游的小分子激动剂，并特异性地逆转了缺铁对红系细胞的抑制作用。此外，一种相关的小分子拮抗剂重述了在铁水平足够高的红系培养中缺铁的影响。该项目的目标是进一步描述铁剥夺与红系发育的谱系特异性调节之间的分子途径，并在小鼠模型系统中研究操纵这一途径的体内后果。这些研究可能为许多对促红细胞生成素治疗耐药的慢性贫血提供新的治疗方法，以及控制红细胞增多症患者的红细胞生成的新方法。项目简介：缺铁是贫血的常见原因，并导致骨髓减少产生红细胞。除了缺铁性贫血，与癌症、肾脏疾病、慢性炎症和衰老相关的贫血也与骨髓产生的红细胞受损有关。后一种贫血的发生部分是由于铁从储存细胞到骨髓中的红细胞前体的运输不足。特别是，红细胞前体感觉到铁缺乏，尽管全身铁储存经常增加。该项目已经确定了骨髓细胞感知铁供应并相应地调节红细胞产生的机制。初步研究发现了一种化合物，可以逆转或模仿骨髓细胞对铁供应减少的反应。因此，这些研究为治疗几种类型的慢性贫血和治疗与红细胞过度产生有关的疾病，如红细胞增多症提供了新的方法。

DESCRIPTION (provided by applicant): Iron deficiency represents one of the most common human nutritional deficiencies in the world but remains surprisingly poorly characterized with regard to its effects on organ physiology. One of the most prominent clinical consequences of this condition consists of a lineage-selective suppression of marrow red cell production, even in the face of high serum erythropoietin levels. The resulting blood abnormality consists of an isolated anemia, with sparing of white blood cell and platelet levels. The erythroid suppression by iron deficiency provides a rheostatic response permitting the adjustment of iron utilization in response to available stores. A further understanding of the underlying pathway has clinical significance for several reasons. Firstly, this pathway also contributes to anemias other than in iron deficiency, such as those associated with chronic inflammation, cancer, and renal disease, conditions marked by defective iron transfer from storage to erythroid compartments. Secondly, this pathway has been purposefully harnessed to limit neoplastic proliferation in polycythemia vera, where therapeutic induction of iron deficiency restrains the clonal expansion of the erythroid compartment. Thirdly, potential treatments or conditions that override this regulatory mechanism could precipitate clinical deterioration in patients with true, severe iron deficiency. Using a novel model system of primary human hematopoietic cultures with defined levels of transferrin saturation, critical signaling targets in this pathway have been identified. In particular, clinically relevant levels of iron deprivation selectively inactivate, i.e. in an erythroid lineage-specific manner, the signaling activity of a specific class of enzymes. This effect occurs through functional inactivation of specific prosthetic groups within these enzymes and not through diminished protein expression. A retroviral genetic screen has identified a specific factor which acts upstream of these enzymes and confers on erythroid progenitors complete resistance to the effects of physiologic iron deprivation. A small molecule agonist which acts downstream of these enzymes has been identified and specifically reverses the erythroid inhibitory effects of iron deprivation. In addition, a related small molecule antagonist recapitulates the effects of iron deprivation in erythroid cultures with adequate iron levels. The goals of this project are to delineate further the molecular pathway that links iron deprivation to lineage specific regulation of erythroid development and to study in a murine model system the in vivo consequences of manipulating this pathway. These studies will potentially provide new treatment approaches for many chronic anemias resistant to erythropoietin therapy, as well as a novel means for controlling erythropoiesis in patients with polycythemia. Project Narrative: Iron deficiency represents a frequent cause of anemia and causes the bone marrow to decrease production of red blood cells. In addition to iron deficiency anemia, anemias associated with cancer, kidney disease, chronic inflammation, and aging also are associated with impaired red cell production by the bone marrow. These latter anemias arise in part because of inadequate transport of iron from storage cells to the red cell precursors in the marrow. In particular, red cell precursors sense an iron deficiency even though total body iron stores are frequently increased. This project has identified the mechanisms by which bone marrow cells sense iron availability and adjust red cell production accordingly. Preliminary studies have led to compounds which can either reverse or mimic the response of marrow cells to diminished iron availability. These studies therefore offer novel approaches for the treatment of several types of chronic anemia and for the treatment of diseases associated with excessive red cell production such as polycythemia.