Analysis of PU.1 Function in Hematopoiesis

PU.1造血功能分析

• 批准号: 7218628
• 负责人: Edward W Scott
• 金额: $ 29.18万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218628
• 关键词: Acute Erythroblastic Leukemia; Address; Adult; B-Lymphocytes; Back; Biological Assay; Blood; Blood Vessels; Bone Marrow; Brain; Catalytic RNA; Cells; Commit; Communities; Data; Development; Embryo; Engraftment; Environment; Erythrocytes; Erythroid; FUS-1 Protein; Fetal Liver; Gene Expression; Genes; Hematopoiesis; Hematopoietic System; Hematopoietic stem cells; Hepatocyte; Knock-in Mouse; LacZ Genes; Link; Liver; Liver Regeneration; Maintenance; Marrow; Modeling; Multipotent Stem Cells; Mus; Myelogenous; Oncogenes; Phenotype; Play; Regulation; Retroviridae; Role; Stem cell transplant; Stem cells; System; T-Lymphocyte; Tamoxifen; Transplantation; adult stem cell; base; fetal; insight; macrophage; oval cell; progenitor; stem cell fate; tool; transcription factor; Acute Erythroblastic Leukemia; Address; Adult; B-Lymphocytes; Back; Biological Assay; Blood; Blood Vessels; Bone Marrow; Brain; Catalytic RNA; Cells; Commit; Communities; Data; Development; Embryo; Engraftment; Environment; Erythrocytes; Erythroid; FUS-1 Protein; Fetal Liver; Gene Expression; Genes; Hematopoiesis; Hematopoietic System; Hematopoietic stem cells; Hepatocyte; Knock-in Mouse; LacZ Genes; Link; Liver; Liver Regeneration; Maintenance; Marrow; Modeling; Multipotent Stem Cells; Mus; Myelogenous; Oncogenes; Phenotype; Play; Regulation; Retroviridae; Role; Stem cell transplant; Stem cells; System; T-Lymphocyte; Tamoxifen; Transplantation; adult stem cell; base; fetal; insight; macrophage; oval cell; progenitor; stem cell fate; tool; transcription factor

DESCRIPTION (provided by applicant): PU.1 is a transcription factor that plays a critical role throughout hematopoiesis. PU.1 was initially described as the causative oncogene in murine erythroleukemias (28). PU.1 is absolutely required for the development of several myeloid lineages as well as B lymphocytes. In these lineages PU.1 regulates the expression of many genes required for terminally differentiated cells to function (reviewed in (9)). PU.1 also plays a role in the development of lineages such as T lymphocytes and red blood cells where PU.1 is not expressed in mature cells. In these lineages PU.1 is expressed in early progenitors and facilitates their differentiation (15, 40). Indeed, PU.1 even plays a pivotal role in the hematopoietic stem cell. It is required for the proper engraftment and maintenance of HSC in the bone marrow microenvironment (8). As a community we still have a very limited understanding of how HSC progress to become lineage committed progenitors that give rise to the distinct functional cells of the hematopoietic system. We know that developmental changes take place in the HSC and that a variety of multipotent progenitors are produced that lack the ability to self-renew. In addition, we have recently proven that adult HSC can robustly function as hemangioblasts (13) - that is make both blood and blood vessels. We have also developed a new model for hematopoietic stem cell (LSC or oval cell) based liver regeneration in the mouse. In this system PU.1-/- HSC produce hepatocytes better than WT HSC. This may be due to the inability of PU.1-/- HSC to make blood, thereby being encouraged to make liver. To control and follow PU.1 function we have knocked-in a Tamoxifen inducible PU.1 fusion protein (PUERT) and both gfp and LacZ to the PU.1 locus. These models and tools will allow us to further dissect the role of PU.1 in stem cell fate and differentiation. In this proposal we will address the following Specific Aims: Aim 1. Is PU.1 linked to the initial development of the definitive and transplantable HSC? Aim 2. Define the role of PU.1 in the transition from fetal HSC to adult HSC phenotype? Is this transition reversible? Is PU.1 required to establish marrow hematopoiesis? Aim 3. Does PU.1 influence the developmental fate of adult stem cells?

描述（由申请人提供）：PU.1是一个转录因子，在整个造血症中起着至关重要的作用。 PU.1最初被描述为鼠红血球血压素中的致病性癌基因（28）。 PU.1绝对需要开发几种髓样谱系和B淋巴细胞。在这些谱系中，PU.1调节终末分化细胞发挥作用所需的许多基因的表达（在（9）中综述）。 PU.1在谱系的发展中也起作用，例如T淋巴细胞和红细胞，其中PU.1在成熟细胞中未表达。在这些谱系中，PU.1在早期的祖细胞中表达，并促进了它们的分化（15、40）。实际上，PU.1甚至在造血干细胞中起关键作用。在骨髓微环境中适当植入和维持HSC所必需的（8）。作为一个社区，我们仍然对HSC如何发展成为谱系致力的祖细胞的了解非常有限，从而导致造血系统的独特功能细胞。我们知道，发育变化发生在HSC中，并且产生了缺乏自我更新能力的各种多能祖细胞。此外，我们最近证明，成年HSC可以牢固地充当血管母细胞（13），即既可以使血管和血管都产生。我们还开发了一种基于小鼠造血干细胞（LSC或椭圆形细胞）的肝脏再生的新模型。在此系统中，PU.1 - / - HSC比WT HSC更好地产生肝细胞。这可能是由于PU.1 - / - HSC无法献血的原因，因此被鼓励制作肝脏。为了控制和遵循PU.1功能，我们将他莫昔芬诱导的PU.1融合蛋白（PUERT）以及GFP和LACZ撞到了PU.1基因座。这些模型和工具将使我们能够进一步剖析PU.1在干细胞命运和分化中的作用。在此提案中，我们将解决以下具体目标：目标1。PU.1与确定和可移植的HSC的初始发展有关吗？ AIM 2。定义PU.1在从胎儿HSC到成人HSC表型的过渡中的作用？这种过渡可逆吗？建立骨髓造血需要PU.1吗？ AIM 3。PU.1是否影响成年干细胞的发育命运？