Iron Deficiency: Molecular and Cellular Consequences

缺铁：分子和细胞后果

基本信息

批准号：
7563297
负责人：
Adam N. Goldfarb
金额：
$ 32.13万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/7563297
关键词：
3&apos Untranslated Regions Aconitate Hydratase Aging Agonist Anemia Animal Model Antidotes Binding Biological Models Blood Blood Platelets Bone Marrow Bone Marrow Cells Calcium Gluconate Cells Chronic Chronic Kidney Failure Citrates Clinical Clonal Expansion Cysteine Deterioration Development Disease Down-Regulation Enzymes Erythrocytes Erythroid Erythropoiesis Erythropoietin Evaluation Face Fluoroacetates Genetic Screening Goals Government Hematopoietic Human Inflammation Iron Iron deficiency anemia Isocitrates Kidney Diseases Leukocytes Link Malignant Neoplasms Malnutrition Marrow Messenger RNA Molecular Molecular Profiling Mus NADP Organ Pathway interactions Patients Persons Physiological Physiology Polycythemia Polycythemia Vera Production Prosthesis Proteins Regulation Research Resistance Role Second Messenger Systems Serum Signal Transduction Signaling Molecule Sodium Source Staging Succinates Sulfur Therapeutic Toxic effect Transferrin Transgenic Organisms clinically relevant clinically significant deprivation erythroid differentiation fluorocitrate in vivo inhibitor/antagonist isocitrate neoplastic novel novel strategies progenitor protein expression response second messenger small molecule

项目摘要

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然很少得到表征。这种情况最显着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较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较低。缺铁引起的红细胞抑制提供了变阻反应，允许根据可用的储存来调整铁的利用。出于多种原因，进一步了解潜在途径具有临床意义。首先，除了缺铁之外，该途径还会导致贫血，例如与慢性炎症、癌症和肾脏疾病相关的贫血，这些疾病的特征是铁从储存到红细胞室的转移有缺陷。其次，该途径已被有目的地利用来限制真性红细胞增多症的肿瘤增殖，其中治疗性诱导缺铁可抑制红细胞室的克隆扩张。第三，超越这种调节机制的潜在治疗或条件可能会导致真正严重缺铁的患者临床恶化。使用具有明确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。特别是，临床相关水平的缺铁选择性地失活（即以红系谱系特异性方式）特定类别酶的信号传导活性。这种效应是通过这些酶内特定辅基的功能失活而不是通过蛋白质表达减少而发生的。逆转录病毒遗传筛选已鉴定出一种特定因子，该因子作用于这些酶的上游，并赋予红系祖细胞对生理性缺铁影响的完全抵抗力。已鉴定出一种作用于这些酶下游的小分子激动剂，可特异性逆转缺铁引起的红细胞抑制作用。此外，一种相关的小分子拮抗剂重现了铁水平充足的红细胞培养物中缺铁的影响。该项目的目标是进一步描绘将缺铁与红细胞发育的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红细胞生成的新方法。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。除了缺铁性贫血外，与癌症、肾病、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。后者贫血的发生部分是由于铁从储存细胞到骨髓中红细胞前体的运输不充分。特别是，即使全身铁储存经常增加，红细胞前体细胞也会感觉到缺铁。该项目已经确定了骨髓细胞感知铁可用性并相应调整红细胞生成的机制。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以及治疗与红细胞生成过多相关的疾病（例如红细胞增多症）提供了新方法。