Molecular Regulation of Erythroid Differentiation

红细胞分化的分子调控

基本信息

批准号：
7564295
负责人：
Min Chen
金额：
$ 34.54万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-15 至 2013-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): During mammalian erythropoiesis, erythroid progenitors differentiate into erythroblasts, followed by the removal of the nucleus and organelles to develop into mature erythrocytes. Although the morphological changes associated with different stages of erythropoiesis have been well characterized, the precise molecular mechanisms governing these processes remain to be determined. A Bcl-2 family member, Nix/Bnip3L, has been found to regulate mitochondrial clearance in differentiating erythroid cells. In Nix-deficient red blood cells, the formation of autophagosomes proceeded normally. However, the sequestration of mitochondria into autophagosomes was defective. Experiments are proposed to test the hypothesis that Nix regulates the targeting of mitochondria into autophagosomes for clearance during terminal erythroid differentiation, and erythrocytes with abnormal retention of mitochondria due to defective mitochondrial autophagy are prone to oxidative stress, leading to increased cell turnover and hemolytic anemia. Aim 1. The hypothesis that Nix is required for the mitochondrial autophagy, but not other aspects of erythroid maturation, will be studied using mice deficient in Nix or autophagy and erythroleukemic cell line. Aim 2. Whether erythrocytes deficient in mitochondrial autophagy are more susceptible to oxidative stress-induced apoptosis will be examined. Aim 3. Downstream molecules mediating Nix-induced mitochondrial autophagy will be studied using immunoprecipitation and proteomics approach. Defects in erythroid maturation have been found to be associated with anemia. By determining the molecular regulation of mitochondrial autophagy responsible for mitochondrial removal during erythroid maturation, we will gain insights into the regulation of erythropoiesis under both normal and disease settings. This will lead to better understanding of the pathogenesis of hemotological disorders associated with defective erythroid maturation. It may also facilitate the development of therapeutic approaches to treat these disorders. PUBLIC HEALTH RELEVANCE: This project seeks to investigate molecular regulation of mitochondrial autophagy during erythroid maturation. This will help gain insights into the regulation of erythropoiesis under both normal and disease settings. The proposed studies may lead to better understanding of the pathogenesis of hemotological disorders associated with defective erythroid maturation.

描述（由申请人提供）：在哺乳动物红细胞生成期间，红细胞祖细胞分化为红细胞，然后去除细胞核和细胞器以发展成成熟的红细胞。尽管与不同阶段的红细胞生成阶段相关的形态学变化已经很好地表征了，但管理这些过程的精确分子机制仍有待确定。已经发现Bcl-2家族成员NIX/BNIP3L可以调节分化红细胞细胞的线粒体清除。在缺乏尼克斯的红细胞中，自噬体的形成正常进行。然而，线粒体将线粒体隔离为自噬体是有缺陷的。提出了实验来检验以下假设：NIX调节线粒体靶向自噬小体，以在终末红细胞分化过程中清除，并且由于线粒体自噬的缺陷而导致线粒体保留异常，导致细胞的氧化胁迫，导致细胞的氧化度增加，导致细胞的氧化和hymemelothe，并导致了氧气的氧化和hymemelositial and，而线粒体保留异常。目的1。将使用缺乏NIX或自噬和红血球细胞系缺乏的小鼠研究线粒体自噬所需的NIX，但没有其他方面的nix。目标2。将检查缺乏线粒体自噬的红细胞更容易受到氧化应激诱导的细胞凋亡的影响。 AIM 3。将使用免疫沉淀和蛋白质组学方法研究介导NIX诱导的线粒体自噬的下游分子。发现红细胞成熟的缺陷与贫血有关。通过确定线粒体自噬的分子调节负责线粒体去除过程中的分子自噬，我们将深入了解正常和疾病环境下红细胞生成的调节。这将使人们更好地理解与缺陷的红细胞成熟有关的血液学疾病的发病机理。它还可能促进治疗这些疾病的治疗方法的发展。公共卫生相关性：该项目旨在调查红细胞成熟期间线粒体自噬的分子调节。这将有助于洞悉正常和疾病环境下的红细胞生成的调节。拟议的研究可能会更好地理解与缺陷红牙性成熟有关的血液学疾病的发病机理。