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

• 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
• 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

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.

项目摘要 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 通过描述负责增强造血茎的分子机制来造成造血损伤 细胞（HSC）自我更新和生存。放射治疗通常会导致急性造血 抑制，但也是长期的骨髓（BM）损伤。迄今为止，尚未开发出有效的治疗 预防或治疗这些病理后果。增强HSC生存并维持其基因组 辐射时的完整性对于保留HSC自我更新功能至关重要 辐射引起的BM损伤。但是，调节HSC存活和自我更新的分子机制 定义不当。 HSC数量和功能表现出自然变化，并且潜在的遗传多样性 是HSC功能调节涉及的重要但未知的机制。乳胶（LXN）是 以前被确定为第一个干细胞调节基因，其自然变异对 HSC种群大小在不同的小鼠菌株中。在初步研究中，构成基因消融方法 开发以定义LXN在HSC和造血中的作用在正常和辐射应力条件下。 结果表明，LXN失活保护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敲除小鼠在单一或分馏后不会出现血液学恶性肿瘤 辐射剂量。从机械上讲，LXN在体内灭活会增加HSC的自我更新和存活。在 分子水平，我们发表的初步工作表明核糖体蛋白亚基3（RPS3）是一种新颖 LXN结合蛋白和LXN过表达抑制RPS3活性，从而提高了辐射敏感性和 毒性。另外，人类HSC/HPC的数量与LXN表达水平负相关， 表明LXN在调节人造血中的潜在作用。这些发现导致了假设 LXN保持体内稳态HSC和造血和LXN功能的抑制可防止 辐射诱导的造血损伤通过RPS3依赖性疾病途径。具体目的是：1） 确定LXN失活增强HSC存活和自我更新的细胞机制 赋予放射保护，2）确定LXN灭活增强LXN-RPS3-的分子机制 NF-KB Prosurvival途径，3）确定LXN在降低人造血细胞毒性中的作用 因辐射损伤。这项研究将提高对关键但研究的机制的理解 参与HSC功能和自我更新的自然调节剂。通过使用鼠标和人类模型系统 以及最先进的分子和基因组技术，拟议研究的发现可能有助于 开发基于机制的新型治疗策略，以防止辐射引起的BM损伤， 这可能对接受癌症治疗和BM移植的患者有益。