Iron Deficiency: Molecular and Cellular Consequences

缺铁：分子和细胞后果

• 批准号: 7760964
• 负责人: Adam N. Goldfarb
• 金额: $ 31.81万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760964
• 关键词: Aging; Agonist; Anemia; Biological Models; Blood; Blood Platelets; Bone Marrow; Bone Marrow Cells; Cells; Chronic; Chronic Kidney Failure; Clinical; Clonal Expansion; Deterioration; Development; Disease; Enzymes; Erythrocytes; Erythroid; Erythropoiesis; Erythropoietin; Evaluation; Face; Genetic Screening; Goals; Government; Hematopoietic; Human; Inflammation; Iron; Iron deficiency anemia; Kidney Diseases; Leukocytes; Link; Malignant Neoplasms; Malnutrition; Marrow; Molecular; Mus; Names; Organ; Pathway interactions; Patients; Persons; Physiological; Physiology; Polycythemia; Polycythemia Vera; Principal Investigator; Production; Prosthesis; Regulation; Research; Resistance; Serum; Signal Transduction; Therapeutic; Transferrin; clinically relevant; clinically significant; deprivation; in vivo; neoplastic; novel; novel strategies; progenitor; programs; protein expression; response; small molecule

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.

描述（由申请人提供）：缺铁是世界上最常见的人类营养缺乏症之一，但令人惊讶的是，其对器官生理学的影响仍缺乏表征。这种疾病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，即使在高血清促红细胞生成素水平的情况下也是如此。由此导致的血液异常包括孤立性贫血，白色血细胞和血小板水平减少。由铁缺乏引起的红细胞抑制提供了一种变阻反应，允许响应于可利用的储存来调节铁的利用。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，该途径也有助于贫血而不是缺铁，例如与慢性炎症、癌症和肾病相关的贫血，这些疾病的特征是铁从储存区转移到红细胞区室的缺陷。其次，该途径已被有目的地利用来限制真性红细胞增多症中的肿瘤增殖，其中铁缺乏的治疗诱导抑制红细胞区室的克隆扩增。第三，潜在的治疗或条件，推翻这一调节机制可能会加速临床恶化的患者真正的，严重的缺铁。使用具有确定转铁蛋白饱和水平的原代人类造血培养物的新型模型系统，已经确定了该途径中的关键信号传导靶点。特别地，临床相关水平的铁剥夺选择性地抑制，即以红系特异性方式抑制特定类别酶的信号传导活性。这种作用是通过这些酶中特定辅基的功能失活而不是通过减少蛋白质表达而发生的。逆转录病毒遗传筛选已经鉴定出一种特异性因子，其作用于这些酶的上游，并赋予红系祖细胞对生理性缺铁的影响的完全抗性。已经鉴定了在这些酶下游起作用的小分子激动剂，并且其特异性逆转铁剥夺的红细胞抑制作用。此外，一种相关的小分子拮抗剂概括了在具有足够铁水平的红系培养物中铁剥夺的作用。该项目的目标是进一步描绘的分子途径，铁剥夺的红系细胞发育的谱系特异性调节和研究在小鼠模型系统中的操纵这一途径的体内后果。这些研究将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，并为控制红细胞增多症患者的红细胞生成提供新的手段。项目叙述：缺铁是贫血的常见原因，并导致骨髓减少红细胞的产生。除缺铁性贫血外，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红细胞受损有关。后一种贫血的发生部分是由于骨髓中贮存细胞向红细胞前体的铁转运不足。特别是，红细胞前体感觉到缺铁，即使全身铁储备经常增加。该项目已经确定了骨髓细胞感知铁可用性并相应地调节红细胞产生的机制。初步研究已经产生了可以逆转或模拟骨髓细胞对铁可用性减少的反应的化合物。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。