Regulatory Role of Iron in Hematopoiesis

铁在造血中的调节作用

基本信息

批准号：
7442292
负责人：
GRANT C BULLOCK
金额：
$ 5.59万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-14 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7442292
关键词：
Affect Anemia Apoptosis Back Blood Platelets Caspase Caspase Inhibitor Cell Cycle Cell Death Cell division Cell model Clinical Clonal Expansion Condition Data Deterioration Disease Down-Regulation Erythrocytes Erythroid Erythropoiesis Erythropoietin Ferritin Goals Growth Growth Factor Heat-Shock Proteins 70 Hematopoiesis Hematopoietic Hematopoietic stem cells Human Iron Iron deficiency anemia MAPK8 gene Malignant neoplasm of kidney Mediating Molecular Pancytopenia Pathologic Pathway interactions Patients Peripheral Blood Stem Cell Phenotype Physiological Play Polycythemia Vera Production Refractory Refractory anemias Regulation Renal carcinoma Retroviral Vector Risk Role Signal Pathway Signal Transduction Staging System Testing Thrombocytopenia Validation bone marrow hyperplasia chemotherapy clinically relevant deprivation design erythroid differentiation gamma secretase human GATA1 protein insight interest neoplastic notch protein novel prevent progenitor research study response secretase therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Iron deficiency anemia is one of the most common forms of anemia and reduces the efficacy of erythropoietin therapy. Iron deficiency also is induced during the treatment of polycythemia vera because of the block in erythropoiesis induced during iron depletion. The negative effects of iron deficiency override both normal and enforced growth factor signaling. Preliminary data suggests that iron deficiency blocks erythroid differentiation at an early stage by increasing cell death and slowing cell division. To test this hypothesis, we propose two aims to further our understanding. First, we will use a physiologically relevant human peripheral blood stem cell model of iron deficiency to characterize erythroid differentiation, cell cycle effects and apoptosis. Second, we will determine what molecules affect erythropoiesis during iron deficiency. Key molecules known to be important in cell death and survival have been identified in preliminary experiments. The roles that these factors play will be determined by inhibition or add-back experiments using retroviral vectors. These experiments will provide insight into how iron regulates erythropoiesis and may provide novel targets for the treatment of anemia and thrombocytopenia.

描述（由申请人提供）：缺铁性贫血是最常见的贫血形式之一，会降低促红细胞生成素治疗的功效。在治疗真性红细胞增多症期间也会引起缺铁，因为铁缺乏期间会导致红细胞生成受阻。缺铁的负面影响超越了正常和强制的生长因子信号传导。初步数据表明，缺铁会通过增加细胞死亡和减慢细胞分裂来阻止早期红细胞分化。为了检验这一假设，我们提出了两个目标来加深我们的理解。首先，我们将使用生理相关的缺铁人类外周血干细胞模型来表征红细胞分化、细胞周期效应和细胞凋亡。其次，我们将确定哪些分子在缺铁期间影响红细胞生成。初步实验已经鉴定出已知对细胞死亡和存活很重要的关键分子。这些因素所起的作用将通过使用逆转录病毒载体的抑制或回加实验来确定。这些实验将深入了解铁如何调节红细胞生成，并可能为治疗贫血和血小板减少症提供新的靶点。