Control of HSC proliferation and migration by the transcription factor EGR1

转录因子 EGR1 控制 HSC 增殖和迁移

基本信息

批准号：
8386665
负责人：
AMY JO WAGERS
金额：
$ 38.05万
依托单位：
JOSLIN DIABETES CENTER
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：
2009-01-16 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8386665
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 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

项目摘要

Project Summary: 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.

项目摘要： 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在调节血液活性中发挥了意外而有趣的作用。形成造血干细胞（HSC）。特别是，我们广泛的初步数据表明EGR1 通常，既有限制HSC增殖的功能，也可以促进BM生态位的HSC保留率。这些发现很重要，原因有几个。首先，EGR1代表仅有的少数已知 HSC静止的调节剂，这对于保留HSC功能至关重要。此外，egr1代表首先确定了HSC迁移的转录调节剂，这表明针对此因素可能会提供新颖诱导干细胞动员进行临床移植的途径。最后，最引人注目的是，这一点的作用在确定HSC的增殖和解剖学定位时，单个基因揭示了一种新颖和控制干细胞数的潜在广泛作用机制，使干细胞分裂是分子的与在利基市场中的保留协调。因此，egr1 - / - 鼠标为发现新的和重要的见解提供了一个非凡的机会 HSC及其临床应用的基本特性。通过两个集中和补充具体目的，本应用程序中提出的工作将（1）通过功能分析确定stem是否是细胞调节因子BMI1代表负责EGR1介导的HSC影响的关键靶基因增殖和定位，（2）识别并在功能上验证EGR1的其他新目标调节HSC活性，（3）阐明了自发动员的细胞机制 Egr1 - / - 小鼠中的LT-HSC。因此，这些研究将EGR1和EGR1 - / - 小鼠作为唯一模型系统的优势回答有关HSC功能的分子和细胞调节的长期问题。