Control of HSC proliferation and migration by the transcription factor EGR1

转录因子 EGR1 控制 HSC 增殖和迁移

• 批准号: 7996588
• 负责人: AMY JO WAGERS
• 金额: $ 40.38万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-16 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996588
• 关键词: Animals; BMI1 gene; Binding; Biological; Biological Assay; Biological Models; Blood; Blood Cells; Blood Circulation; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Candidate Disease Gene; Cell Count; Cell Maintenance; Cell Proliferation; Cell physiology; Cells; Clinical; Data; Employee Strikes; Engraftment; Environment; Exhibits; Frequencies; Gene Expression; Gene Family; Gene Targeting; Genes; Genetic; Growth; Harvest; Health; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Homeostasis; Homing; Immediate-Early Genes; Infusion procedures; Label; Life; Literature; Longevity; Malignant - descriptor; Mediating; Methods; Molecular; Mus; Non-Malignant; Organ; Osteoclasts; Parabiosis; Pathway interactions; Polycomb; Process; Production; Property; Proteins; Publishing; RNA Interference; Repression; Role; Speed; Stem cell transplant; Stem cells; Testing; Transplantation; Work; Zinc Fingers; base; bone; cell growth regulation; cell motility; cell type; chromatin immunoprecipitation; clinical application; gene interaction; improved; in vivo; insight; migration; novel; peripheral blood; promoter; research study; response; self-renewal; stem cell division; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): EGR1 (Early Growth Response 1) is a well-known transcription factor of the immediate early gene family. My lab recently discovered an unexpected and intriguing role for EGR1 in regulating the activity of blood- forming hematopoietic stem cells (HSC). In particular, our extensive Preliminary Data demonstrate that EGR1 normally functions both to limit HSC proliferation and to promote HSC retention in the BM niche. These findings are significant for several reasons. First, EGR1 represents one of only a few known regulators of HSC quiescence, which is critical in preserving HSC function. Moreover, EGR1 represents the first identified transcriptional regulator of HSC migration, suggesting that targeting this factor may provide novel avenues to inducing stem cell mobilization for clinical transplant. Finally, and most remarkably, the role of this single gene in determining both the proliferation and anatomical localization of HSC reveals a novel and potentially broadly acting mechanism for controlling stem cell number whereby stem cell division is molecularly coordinated with retention in the niche. Egr1-/- mice thus present an extraordinary opportunity for discovering new and important insights into the fundamental properties of HSC and their clinical applications. Through two focused and complementary Specific Aims, the work proposed in this application will (1) determine by functional analyses whether the stem cell regulatory factor Bmi1 represents a key target gene responsible for EGR1-mediated effects on HSC proliferation and localization, (2) identify and functionally validate additional, novel targets of EGR1 that regulate HSC activity, and (3) elucidate the cellular mechanism(s) underlying the spontaneous mobilization of LT-HSC in Egr1-/- mice. These studies thus take advantage of EGR1 and Egr1-/- mice as unique model system to answer long-standing questions about the molecular and cellular regulation of HSC function. PUBLIC HEALTH RELEVANCE: Egr1 represents the first known transcriptional regulator of both HSC migration and proliferation. Thus, identification of the Egr1-regulated pathways active in HSC will be vital for developing a mechanistic understanding of these processes and their role in stem cell function. These findings will have significant implications both for understanding the normal, homeostatic control of HSC activity in blood formation and for manipulating stem cell activity clinically to improve the efficiency of HSC mobilization for donor cell harvest and to speed hematopoietic engraftment following transplantation.

描述（由申请人提供）：EGR1（早期生长反应1）是早期基因家族的众所周知的转录因子。我的实验室最近发现EGR1在调节血液形成造血干细胞的活性（HSC）中发挥了出乎意料而有趣的作用。特别是，我们广泛的初步数据表明，EGR1通常在限制HSC增殖并促进BM壁re中的HSC保留率。这些发现很重要，原因有几个。首先，EGR1代表了HSC静止的仅有的少数已知调节剂之一，这对于保留HSC功能至关重要。此外，EGR1代表了HSC迁移的第一个鉴定的转录调节剂，这表明靶向该因子可能会为诱导干细胞动员临床移植提供新的途径。最后，而且最引人注目的是，该单个基因在确定HSC的增殖和解剖学定位中的作用揭示了一种新型且潜在的作用机制，用于控制干细胞数量，从而使干细胞分裂分子在利基市场中的保留率分子协调。因此，EGR1 - / - 小鼠为发现有关HSC及其临床应用的基本特性的新的重要见解提供了非凡的机会。通过两个集中和互补的特定目的，本应用中提出的工作将（1）通过功能分析确定干细胞调节因子BMI1是否代表了负责EGR1介导的HSC增殖和定位效应的关键靶基因，（2）识别和功能验证EGR1的新型egr1和（3）细胞（3）细胞（3）的新靶标（3） EGR1 - / - 小鼠中LT-HSC的动员。因此，这些研究利用EGR1和EGR1 - / - 小鼠作为独特的模型系统，回答有关HSC功能的分子和细胞调节的长期问题。公共卫生相关性：EGR1代表了HSC迁移和增殖的第一个已知的转录调节剂。因此，对HSC中活性的EGR1调节途径的鉴定对于发展对这些过程的机械理解及其在干细胞功能中的作用至关重要。这些发现将对血液形成中HSC活性的正常，稳态控制以及在临床上操纵干细胞活性的正常稳态控制具有重要意义，以提高HSC动员对供体细胞收获的效率，并在移植后加快造血性造血性植入。