Novel Determinants of Terminal Erythroid Maturation

红细胞终末成熟的新决定因素

基本信息

批准号：
8550827
负责人：
Emery H Bresnick
金额：
$ 38万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8550827
关键词：
1-Phosphatidylinositol 3-Kinase AKT Signaling Pathway Address Anemia Autophagocytosis Autophagosome Biological Blood Cell Cycle Cell Differentiation process Cell Maturation Cell physiology Cells Chromatin Clinical Consumption Cytoplasm Development Disease Ensure Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis Functional disorder Gene Activation Gene Expression Genes Genetic Hematopoietic Higher Order Chromatin Structure Human Genome Longevity Maintenance Mediating Mitochondria Modeling Molecular Mus Organelles Oxidative Stress Pathway interactions Phosphorylation Physiological Polycythemia Vera Process Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Regulation Signal Transduction Site Staging Stem cells Stress System Testing Thalassemia Therapeutic Transfusion abstracting base chromatin modification feeding human FRAP1 protein human GATA1 protein improved in vivo insight mTOR inhibition mouse genome novel stem transcription factor

项目摘要

DESCRIPTION (provided by applicant): Elucidating mechanisms that regulate erythroid cell maturation is critical for devising targeted therapies for red cell disorders including thalassemias, polycythemia vera and anemias, and for developing strategies to generate red blood cells for clinical transfusion. The PI3-kinase-AKT pathway promotes and suppresses erythroid maturation. The inhibitory mechanism involves AKT-mediated phosphorylation of FoxO3, which leads to its sequestration in the cytoplasm. FoxO3 is upregulated/activated during erythroid maturation and by oxidative stress and controls the erythroid cell cycle and maturation, red blood cell lifespan, and protects against oxidative stress. We developed evidence that the serine/threonine kinase mTOR engages in crosstalk with FoxO3 to control erythroid maturation. Mechanisms underlying FoxO3- mTOR crosstalk in any context are poorly understood. FoxO3 and mTOR were known to have critical independent functions to control autophagy in non-erythroid cells. Autophagy mediates the consumption of damaged cellular components and differentiation-associated cellular remodeling, including mitochondria disposal as a key step in erythrocyte development. We discovered that FoxO3 facilitates GATA-1-instigated autophagy gene activation and accumulation of the autophagosome during erythroid maturation. GATA-1 also activates autophagy by directly inducing FoxO3 expression. We hypothesize that GATA-1-FoxO3 cooperativity controls autophagy and is modulated by mTOR signaling, which would constitute a new paradigm with considerable potential for therapeutic modulation of erythropoiesis and understanding erythroid pathophysiologies. The Bresnick and Ghaffari groups will collectively test this hypothesis and elucidate mechanisms. Aim 1 - To elucidate mechanisms underlying FoxO3 regulation of terminal erythroid maturation. We will test the hypothesis that FoxO3 has a critical function to promote autophagy in late erythroid maturation. We will determine whether FoxO3 stimulates autophagy in steady-state and stress erythropoiesis contexts, if oxidative stress influences erythroid maturation by controlling autophagy, and if mTOR-FoxO3 crosstalk regulates autophagy. As inhibition of mTOR signaling improves anemia in a b-thalassemia model, we will address the potential function of autophagy in b-thalassemia. Aim 2 - To discriminate among models to explain how GATA-1 and FoxO3 cooperatively control autophagy and erythroid maturation. We hypothesize that GATA-1-FoxO3 cooperativity represents a physiological mechanism to control erythroid maturation. We will distinguish between models to understand the cooperativity, which conforms to a type I coherent feed-forward loop, and will determine how it contributes to establishment/maintenance of the erythroid genetic network. Given the importance of GATA and FoxO factors for regulating diverse processes, the studies will yield broad mechanistic and biological insights. (End of Abstract)

描述（由申请人提供）：阐明调节红细胞细胞成熟的机制对于设计针对红细胞疾病的靶向疗法至关重要，包括thalassemias，多余的Vera和Anemias，以及制定为临床输血产生红细胞的策略。 PI3-激酶-akt途径可促进和抑制红斑成熟。抑制性机制涉及Akt介导的FOXO3磷酸化，从而导致其在细胞质中的隔离。 FOXO3在红系成熟期间和氧化应激期间被上调/激活，并控制红细胞周期和成熟，红细胞寿命，并防止氧化应激。我们开发了丝氨酸/苏氨酸激酶MTOR与FOXO3进行串扰以控制红系成熟的证据。在任何情况下，FOXO3- MTOR串扰的机制尚不清楚。已知FOXO3和MTOR具有关键的独立功能，可以控制非果皮细胞中的自噬。自噬介导了受损的细胞成分的消耗和分化相关的细胞重塑，包括线粒体处置是红细胞发育的关键步骤。我们发现FOXO3促进了GATA-1诱导的自噬基因激活和粒子成熟过程中自噬体的积累。 GATA-1还通过直接诱导FOXO3表达来激活自噬。我们假设GATA-1-FOXO3协作控制自噬，并通过MTOR信号调节，这将构成一种新的范式，具有对促红细胞生成的治疗调节潜力并理解红细胞病理生理学的潜力。布雷斯尼克（Bresnick）和加法里（Ghaffari）组将共同检验这一假设并阐明机制。目的1-阐明末端红斑成熟的FOXO3调节的机制。我们将检验以下假设：FOXO3具有促进胚芽成熟后自噬的关键功能。我们将确定FOXO3在稳态和压力红细胞生成环境中是否刺激自噬，氧化应激是否通过控制自噬会影响红斑成熟，以及是否会调节自噬。随着MTOR信号传导的抑制可以改善B-心助理模型中的贫血，我们将解决自噬在B-杜松子症中的潜在功能。目标2-歧视模型，以解释GATA -1和FOXO3如何合作控制自噬和红系成熟。我们假设GATA-1-FOXO3合作社代表了控制红系成熟的生理机制。我们将区分模型以了解合作性的模型，该模型符合I型相干馈电环路，并将确定其如何促进红细胞遗传网络的建立/维护。鉴于GATA和FOXO因素对调节各种过程的重要性，研究将产生广泛的机械和生物学见解。（抽象的结尾）