Preserving bone marrow niche integrity and function to rejuvenate aged hematopoietic stem cells

保护骨髓生态位的完整性和功能，使老化的造血干细胞恢复活力

• 批准号: 10735925
• 负责人: Jason Mathew Butler
• 金额: $ 65.1万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735925
• 关键词: Activities of Daily Living; Affect; Aging; Animal Model; Award; Biological Assay; Blood; Blood Vessels; Bone Marrow; Cell Maintenance; Cell Therapy; Cells; Clinical Trials; DNA Damage; Data; Defect; Development; Disease; Endothelial Cells; Endothelium; Failure; Foundations; Genes; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Imaging Techniques; Individual; Infusion procedures; Injury; Knockout Mice; Longevity; Mesenchymal Stem Cells; Molecular; Morbidity - disease rate; Mus; Myelosuppression; NTN1 gene; Natural regeneration; Organ; Pathologic; Pathway interactions; Phenotype; Play; Predisposition; Premature aging syndrome; Process; Publishing; Recovery; Regenerative Medicine; Regimen; Rejuvenation; Research; Research Proposals; Resolution; Risk; Role; Scientist; Signal Pathway; Signal Transduction; Source; System; Testing; Therapeutic; Tissues; Vascular System; age related; aged; animal imaging; body system; bone aging; bone preservation; design; endothelial stem cell; experimental study; fitness; functional restoration; healthspan; healthy aging; hematopoietic stem cell expansion; hematopoietic stem cell niche; improved; in vivo; in vivo Model; innovation; insight; mortality; netrin receptor; new therapeutic target; novel; overexpression; permissiveness; preservation; prevent; receptor; repaired; response; self-renewal; stem cell function; stem cells; success; therapeutic development

PROJECT SUMMARY The aging process is associated with an increased risk of failure of therapeutic strategies to treat hematopoietic diseases, which often rely on myelosuppression and transplantation of hematopoietic stem cells (HSCs). There is a substantial need for the development of preventative and therapeutic options to delay the aging process, to rejuvenate tissues/organs, and to enhance regeneration and repair. However, the ability to truly rejuvenate aged HSCs or their supportive niches has eluded scientists. To date, published rejuvenation studies have shown marginal improvements in a few aspects of aged HSC function and have made exaggerated claims of `HSC rejuvenation' without employing assays to stringently evaluate aged stem cells. This research proposal reveals Netrin-1 (NTN1) as a niche-derived signal that can be utilized as a therapeutic that can restore the function of an aged HSC, including its self-renewal capabilities, by reactivating DNA Damage Response (DDR) pathways and resolving DNA damage, a hallmark feature of the aging hematopoietic system. We further define NTN1 as a critical regulator of HSC niche function, where deletion of NTN1 in critical bone marrow (BM) niche constituents leads to a decrease in vascular integrity and mesenchymal stem cell function. This proposal will elucidate the cellular and molecular mechanisms by which aging of the BM niche contributes to the decline of HSC function, as well as validate Netrin-1 as a new therapeutic target whose infusion can enhance, preserve, and rejuvenate an aging hematopoietic system. Specifically, we will: 1) determine which HSC-specific and BM niche-specific NTN1 receptors are critical for rejuvenating the aged hematopoietic system, 2) determine if NTN1 treatment can prevent or temporize the aging process to promote hematopoietic health span and longevity, 3) discover the cellular interactions and molecular mechanisms regulated by NTN1 signaling that are responsible for activating DDR pathways within HSCs and BM niche cells, and 4) test whether in vivo infusion of NTN1 can enhance the regeneration of an aged BM microenvironment following myelosuppression. Our research plan will utilize innovative in vivo animal models and imaging techniques to determine if we can alleviate aging-related pathological hematopoietic phenotypes observed in aged individuals by enhancing NTN1 signaling. Using sophisticated animal models, we will determine the critical cellular sources of NTN1 and its receptors in a cell- specific manner that are required to preserve HSC and niche function during the aging process. The success of this research proposal will open up new avenues for the development of a wide array of therapeutic strategies designed to effectively reverse age-related hematopoietic deficiencies.

项目概要 衰老过程与造血系统治疗策略失败的风险增加有关 疾病，通常依赖于骨髓抑制和造血干细胞（HSC）移植。那里 迫切需要开发预防和治疗方案来延缓衰老过程， 使组织/器官恢复活力，并增强再生和修复。然而，真正能够让老年人返老还童的能力 HSC 或其支持性利基一直困扰着科学家。迄今为止，已发表的复兴研究表明 老年 HSC 功能的某些方面略有改善，并夸大了“HSC”的说法 无需采用严格评估老化干细胞的检测方法即可实现“返老还童”。这项研究计划揭示了 Netrin-1 (NTN1) 作为一种生态位衍生信号，可用作恢复功能的治疗剂 老化的 HSC，包括其自我更新能力，通过重新激活 DNA 损伤反应 (DDR) 途径 并解决 DNA 损伤，这是衰老造血系统的一个标志性特征。我们进一步将 NTN1 定义为 HSC 生态位功能的关键调节因子，其中关键骨髓 (BM) 生态位成分中 NTN1 的缺失 导致血管完整性和间充质干细胞功能下降。该提案将阐明 BM 生态位老化导致 HSC 功能下降的细胞和分子机制， 以及验证 Netrin-1 作为新的治疗靶点，其输注可以增强、保存和恢复活力 老化的造血系统。具体来说，我们将： 1) 确定 HSC 特异性和 BM 利基特异性 NTN1受体对于恢复衰老的造血系统至关重要，2）确定NTN1治疗是否可以 预防或延缓衰老过程，促进造血健康和长寿，3）发现 由负责激活的 NTN1 信号传导调节的细胞相互作用和分子机制 HSC 和 BM 微环境细胞内的 DDR 通路，以及 4) 测试体内输注 NTN1 是否可以增强 骨髓抑制后老化的骨髓微环境的再生。我们的研究计划将利用 创新的体内动物模型和成像技术，以确定我们是否可以缓解与衰老相关的疾病 通过增强 NTN1 信号传导在老年人中观察到病理造血表型。使用 通过复杂的动物模型，我们将确定细胞中 NTN1 及其受体的关键细胞来源- 在衰老过程中保护 HSC 和利基功能所需的特定方式。的成功 该研究提案将为开发多种治疗策略开辟新途径 旨在有效逆转与年龄相关的造血缺陷。