Iron Deficiency: Molecular and Cellular Consequences

描述（由申请人提供）：铁缺乏症是世界上最常见的人类营养缺乏症之一，但其对器官生理的影响却令人惊讶地缺乏特征。这种情况最突出的临床后果之一是骨髓红细胞产生的谱系选择性抑制，即使在血清促红细胞生成素水平高的情况下也是如此。由此产生的血液异常包括孤立性贫血，白细胞和血小板水平减少。铁缺乏对红细胞的抑制提供了一种流变反应，允许根据可用储量调整铁的利用。由于几个原因，进一步了解潜在的途径具有临床意义。首先，除了缺铁以外，这一途径也会导致贫血，如与慢性炎症、癌症和肾脏疾病相关的贫血，这些疾病的特征是铁从储存区转运到红系室的缺陷。其次，这一途径已被有目的地利用来限制真性红细胞增多症的肿瘤增殖，在真性红细胞增多症中，铁缺乏的治疗诱导抑制了红细胞室的克隆扩增。第三，潜在的治疗方法或条件超越这一调节机制，可能导致真正严重缺铁患者的临床恶化。利用一种具有明确转铁蛋白饱和水平的人造血培养的新模型系统，已经确定了该途径中的关键信号靶点。特别是，临床相关水平的铁剥夺选择性地失活，即以红系特异性的方式，一类特定酶的信号活性。这种作用是通过这些酶中特定的假体群的功能失活而发生的，而不是通过减少蛋白质表达。逆转录病毒基因筛选已经确定了一个特定的因子，它作用于这些酶的上游，并赋予红系祖细胞对生理性铁剥夺的完全抗性。一种作用于这些酶下游的小分子激动剂已经被确定，并特异性地逆转铁剥夺对红细胞的抑制作用。此外，一种相关的小分子拮抗剂概括了铁缺乏对红细胞培养的影响。该项目的目标是进一步描述将铁剥夺与红细胞发育谱系特异性调节联系起来的分子途径，并在小鼠模型系统中研究操纵该途径的体内后果。这些研究将有可能为许多对促红细胞生成素治疗有耐药性的慢性贫血提供新的治疗途径，并为控制红细胞增多症患者的红细胞生成提供新的手段。项目说明：缺铁是贫血的常见原因，并导致骨髓减少红细胞的产生。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红细胞生成受损有关。这些后一种贫血的部分原因是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，即使全身铁储量经常增加。这个项目已经确定了骨髓细胞感知铁的可用性并相应地调整红细胞生产的机制。初步的研究已经产生了可以逆转或模拟骨髓细胞对铁可用性降低的反应的化合物。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生成过多相关的疾病（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.