Role of Gab1 and Gab2 in Stress Erythropoiesis

Gab1 和 Gab2 在应激性红细胞生成中的作用

• 批准号: 8439536
• 负责人: Pamela A Giblin
• 金额: $ 22.53万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439536
• 关键词: Acute; Age; Anemia; Anemia due to Chronic Disorder; Apoptosis; BFU-E; BMP4; Binding Sites; Biological; Biological Process; Bone Marrow; CD34 gene; Cell Cycle Arrest; Cell Survival; Cell Therapy; Cell membrane; Cell surface; Cells; Chronic; Data; Defect; Development; Disease; Embryonic Development; Erythroblasts; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Erythropoiesis; Family; Friend Murine Leukemia Virus; GDF15 gene; Human; Hypoxia; Inherited; Intervention; Ligands; Maintenance; Malignant Neoplasms; Manuscripts; Mediating; Modeling; Molecular; Molecular Target; Mus; Phenylhydrazines; Play; Population; Preparation; Process; Property; Public Health; Publishing; Radiation therapy; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Spleen; Stem cells; Stress; TFRC gene; Testing; Time; Transplantation; Treatment-Induced Anemia; Up-Regulation; base; chemotherapy; combat; human disease; insight; leukemia; man; novel; phenylhydrazine; premature; prevent; progenitor; response; scaffold; trait

DESCRIPTION (provided by applicant): Bone marrow steady state erythropoiesis is primarily homeostatic, producing erythrocytes at a constant rate to replace the erythrocytes lost through normal turnover. However, during embryogenesis and in response to anemic stress, new erythrocytes must be produced at an accelerated rate. This process, termed stress erythropoiesis, utilizes a specialized population of stress progenitors that are phenotypically distinct from steady state erythroid progenitors. In preliminary data shown here we demonstrate, for the first time, an essential role for the scaffold proteins, Gab1 and Gab2, in stress erythropoiesis. Scaffold proteins form signaling hubs by integrating the information from a variety of external signals and transforming this information into the appropriate biological response. However, due to the high level of complexity of these scaffolds, the mechanisms by which Gab1 and Gab2 promote distinct biological functions have remained elusive. We demonstrate here that, while Gab1 and Gab2 are highly related, their functions in stress erythropoiesis are non-compensatory. Furthermore, we have developed a novel ex vivo model of stress erythropoiesis in which serially transplantable stress erythroid stem cells undergo specification and expansion, ultimately giving rise to stress BFU-E. Using this approach, we have shown that Gab1 plays an essential role in the differentiation of stress BFU-E from stress erythroid stem cells, as demonstrated by the inability of Gab-deficient cells to upregulate CD71 and Ter119. We also provide evidence that Gab2 plays an essential role in promoting the proliferation and/or survival of stress erythroid progenitors. The studies proposed here will determine the molecular mechanism by which these related scaffolds promote non-redundant functions in stress erythropoiesis. Toward that end, we propose three specific aims. In aim 1, we will test the hypothesis that Recruitment of Shp2 by Gab1 promotes sustained Erk activation at the cell membrane, thus promoting the differentiation of stress BFU-E from stress stem cells. In aim 2, we will test the hypothesis that Gab2 plays an essential role in the activation of Stat3 and the upregulation of Pu.1 expression, thus preventing premature differentiation and promoting survival of differentiating stress erythroid progenitors. Finally, in aim 3 we will test the hypothsis that Gab1 and Gab2 play essential roles in the ex vivo expansion of human stress erythroid progenitors. These studies will provide significant insight into the molecular mechanisms governing the rapid expansion of stress erythroid progenitor cells during times of acute need, and will be essential in the identification of new pharmacological targets as well as the development of novel cell-based therapies for the treatment of acute and chronic anemia. PUBLIC HEALTH RELEVANCE: Hereditary anemias are amongst the most common monogenic traits in man. These diseases, together with anemia from chronic disease or old age, as well as treatment-induced anemia as accompanies chemotherapy or radiation therapy, are significant public health problems. Stress erythropoiesis is the process of replacing lost red blood cells in response to acute need. We have identified novel signaling pathways, which play a central role in stress erythropoiesis, by promoting the differentiation and survival of a specialized population of stress erythroid progenitor cells. The studies proposed herein aim to identify the molecular mechanisms by which these functions are regulated. Understanding the signaling pathways that govern the expansion of stress progenitors will be a critical step in the development of cell-based therapies for combating chronic and acute anemia.

描述(申请人提供)：骨髓稳态红细胞生成主要是动态平衡，以恒定的速率产生红细胞，以取代正常周转过程中丢失的红细胞。然而，在胚胎发育和对贫血应激的反应中，新的红细胞必须以加速的速度产生。这个过程被称为应激红细胞生成，利用了一组特殊的应激前体细胞，这些细胞在表型上不同于稳定状态的红系祖细胞。在这里显示的初步数据中，我们第一次展示了支架蛋白GAB1和GAB2在应激性红细胞生成中的重要作用。支架蛋白通过整合来自各种外部信号的信息，并将这些信息转化为适当的生物反应，形成信号中枢。然而，由于这些支架的高度复杂性，GAB1和Gab2促进不同生物学功能的机制仍然不清楚。我们在这里证明，虽然GAB1和GAB2高度相关，但它们在应激性红细胞生成中的作用是非代偿的。此外，我们开发了一种新的应激性红细胞生成的体外模型，在该模型中，可连续移植的应激性红系干细胞经过规范和扩增，最终产生应激性BFU-E。使用这种方法，我们已经证明了GAB1在应激BFU-E从应激红系干细胞分化中起着重要作用，正如Gab缺陷细胞无法上调CD71和Ter119所证明的那样。我们还提供证据表明，Gab2在促进应激性红系祖细胞的增殖和/或存活方面起着重要作用。本文提出的研究将确定这些相关支架在应激性红细胞生成中促进非多余功能的分子机制。为此，我们提出了三个具体目标。在目标1中，我们将验证GAB1募集Shp2促进细胞膜上持续的ERK激活，从而促进应激BFU-E向应激干细胞分化的假设。在目标2中，我们将检验Gab2在STAT3和STAT3的激活中发挥重要作用的假设 上调PU1的表达，从而防止过早分化，促进分化的应激红系祖细胞存活。最后，在目标3中，我们将测试GAB1和GAB2在人类应激红系祖细胞体外扩增中发挥重要作用的假设。这些研究将为控制应激性红系祖细胞在紧急需要时快速扩张的分子机制提供重要的见解，并将在确定新的药理靶点以及开发治疗急性和慢性贫血的基于细胞的新疗法方面至关重要。 公共卫生相关性：遗传性贫血是人类最常见的单基因特征之一。这些疾病，加上慢性病或老年贫血，以及伴随化疗或放射治疗的治疗引起的贫血，都是重大的公共卫生问题。应激性红血球生成是在紧急情况下替换丢失的红血球的过程。我们已经确定了新的信号通路，通过促进应激红系祖细胞的特殊群体的分化和存活，这些信号通路在应激红系生成中发挥核心作用。本文提出的研究旨在确定调控这些功能的分子机制。了解控制应激祖细胞扩张的信号通路将是开发基于细胞的治疗慢性和急性贫血的关键一步。