Latexin function in the maintenance and regeneration of the hematopoietic system

乳胶素在造血系统的维持和再生中的作用

基本信息

批准号：
9197912
负责人：
Ying Liang
金额：
$ 37.63万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197912
关键词：
Ablation Acute Apoptosis Attenuated Binding Binding Proteins Biological Models Biological Preservation Blood Bone Marrow Bone Marrow Cells Bone Marrow Transplantation CD34 gene Cancer Patient Cell Count Cell Death Cell Survival Cell model Cell physiology Cells Complex DNA Damage Development Exposure to Genes Genetic Genetic Transcription Genetic Variation Genomics Goals Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic System Hematopoietic stem cells Human In Vitro Injury Knockout Mice Late Effects Lead Liquid substance Maintenance Mediating Modeling Molecular Mouse Strains Mus Myelosuppression NF-kappa B Natural regeneration Nuclear Translocation PC3.1 antigen Pathologic Pathway interactions Patients Pharmacology Population Sizes Process Protein Subunits Publishing Quality of life Radiation Radiation Dosage Radiation Injuries Radiation Tolerance Radiation Toxicity Radiation therapy Radioprotection Reactive Oxygen Species Recruitment Activity Regulation Regulator Genes Reporting Research Ribosomal Proteins Role Second Primary Cancers Signal Transduction Solid Stem cells Stress Techniques Therapeutic Variant Work Xenograft procedure base cancer therapy cell injury cell transformation chemotherapy effective therapy functional decline genome integrity in vivo knock-down mortality mouse model novel overexpression p65 preconditioning prevent promoter radiation response radiation-induced injury response self-renewal senescence small hairpin RNA tumor

项目摘要

PROJECT SUMMARY The long-term goal of this study is to develop new strategies to mitigate and protect radiation-induced hematopoietic injury by delineating the molecular mechanisms responsible for enhancing hematopoietic stem cells (HSC) self-renewal and survival. Radiation therapy commonly results in not only acute hematopoietic suppression but also long-term bone marrow (BM) injury. To date, no effective treatment has been developed to prevent or treat these pathological consequences. Enhancing HSC survival and maintaining their genomic integrity upon radiation are crucial for preservation of HSC self-renewal function and for protection against radiation-induced BM injury. However, the molecular mechanisms for regulating HSC survival and self-renewal are not well defined. HSC number and function demonstrate natural variations, and underlying genetic diversity is an important, yet largely unknown, mechanism involved in the regulation of HSC function. Latexin (Lxn) was previously identified as the first stem cell regulatory gene whose natural variation negatively contributes to the HSC population size in different mouse strains. In preliminary studies, constitutive gene ablation approaches were developed to define the role of Lxn in HSCs and hematopoiesis in normal and radiation stress conditions. Results showed that Lxn inactivation protects HSCs and hematopoietic progenitor cells (HPCs) from radiation- induced cell death, thus mitigating acute hematopoietic suppression and conferring a survival advantage. Moreover, Lxn knockout mice do not develop hematological malignancies following single or fractionated dosages of radiation. Mechanistically, Lxn inactivation in vivo increases HSC self-renewal and survival. At the molecular level, our published and preliminary work showed that ribosomal protein subunit 3 (Rps3) is a novel Lxn-binding protein, and Lxn overexpression inhibits Rps3 activity, thus enhancing radiation sensitivity and toxicity. In addition, the number of human HSCs/HPCs negatively correlates with Lxn expression level, indicating the potential role of Lxn in regulating human hematopoiesis. These findings lead to the hypothesis that Lxn maintains homeostatic HSC and hematopoiesis and inhibition of Lxn function protects against radiation-induced hematopoietic injury via Rps3-dependent prosurvival pathways. Specific aims are to: 1) determine the cellular mechanisms by which Lxn inactivation enhances HSC survival and self-renewal and confers radioprotection, 2) identify the molecular mechanisms by which Lxn inactivation enhances Lxn-Rps3- NF-kB prosurvival pathway, and 3) determine the role of Lxn in mitigating human hematopoietic cell toxicity from radiation injury. This research will advance understanding of a critical but understudied mechanism involved in the natural regulator of HSC function and self-renewal. By using mouse and human model systems and state-of-the-art molecular and genomic techniques, findings from the proposed study may facilitate to the development of novel mechanism-based therapeutic strategy to protect against radiation-induced BM injury, which could be beneficial for the patients receiving cancer therapy and BM transplantation.

项目概要这项研究的长期目标是制定新的策略来减轻和保护辐射引起的辐射通过描绘负责增强造血干的分子机制来研究造血损伤细胞（HSC）的自我更新和生存。放射治疗通常不仅会导致急性造血功能损害抑制，而且还有长期的骨髓（BM）损伤。迄今为止，尚未开发出有效的治疗方法预防或治疗这些病理后果。提高 HSC 存活率并维持其基因组辐射时的完整性对于维持 HSC 自我更新功能和防止辐射引起的骨髓损伤。然而，调节 HSC 存活和自我更新的分子机制没有明确定义。 HSC 数量和功能表现出自然变异和潜在的遗传多样性是参与 HSC 功能调节的重要但很大程度上未知的机制。乳胶蛋白 (Lxn) 为先前被确定为第一个干细胞调节基因，其自然变异对不同小鼠品系的 HSC 群体大小。在初步研究中，组成型基因消融方法旨在定义正常和辐射应激条件下 Lxn 在 HSC 和造血中的作用。结果表明，Lxn 失活可保护 HSC 和造血祖细胞 (HPC) 免受辐射- 诱导细胞死亡，从而减轻急性造血抑制并赋予生存优势。此外，Lxn 敲除小鼠在单次或分次治疗后不会出现血液恶性肿瘤。辐射剂量。从机制上讲，Lxn 体内失活可增加 HSC 的自我更新和存活。在在分子水平上，我们发表的和初步的工作表明核糖体蛋白亚基3（Rps3）是一种新型的 Lxn 结合蛋白和 Lxn 过表达抑制 Rps3 活性，从而增强辐射敏感性和毒性。此外，人类 HSC/HPC 的数量与 Lxn 表达水平呈负相关，表明Lxn在调节人类造血中的潜在作用。这些发现引出了以下假设 Lxn 维持 HSC 和造血功能的稳态，抑制 Lxn 功能可以防止通过 Rps3 依赖性促生存途径辐射诱导的造血损伤。具体目标是：1) 确定 Lxn 失活增强 HSC 存活和自我更新的细胞机制提供辐射防护，2) 确定 Lxn 失活增强 Lxn-Rps3- 的分子机制 NF-kB 促生存途径，3) 确定 Lxn 在减轻人类造血细胞毒性中的作用免受辐射损伤。这项研究将增进对关键但尚未充分研究的机制的理解参与 HSC 功能和自我更新的自然调节。通过使用小鼠和人体模型系统以及最先进的分子和基因组技术，拟议研究的结果可能有助于开发新的基于机制的治疗策略以防止辐射引起的骨髓损伤，这可能对接受癌症治疗和骨髓移植的患者有益。