The role of NPY in stress-induced hematopoiesis

NPY 在应激诱导造血中的作用

• 批准号: 10444142
• 负责人: Pratibha Singh
• 金额: $ 39.25万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444142
• 关键词: Acute; Adrenergic Agents; Applications Grants; Blood; Blood Circulation; Blood Vessels; Bone Marrow; CSF3 gene; CXCR4 gene; Cell Count; Cell surface; Cells; Chemotherapy and/or radiation; Chronic; Complication; DNA Damage; Data; Defect; Dipeptidyl-Peptidase IV; Dose; Endogenous Factors; Endothelial Cells; Engraftment; Functional disorder; Generations; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Homing; Human; Immune; Impairment; Inherited; Ionizing radiation; Knockout Mice; Light; Maintenance; Malignant - descriptor; Mediating; Metabolic Diseases; Modeling; Molecular; Mus; Natural regeneration; Neurons; Neuropathy; Neuropeptide Y Receptor; Neurotransmitters; Neutropenia; Non-Malignant; Opportunistic Infections; Outcome; Oxidative Stress; Pathologic; Patients; Peptidyl-Dipeptidase A; Peripheral Nervous System Diseases; Pharmacology; Physiological; Play; Population; Premature aging syndrome; Prevention approach; Production; Radiation therapy; Reactive Oxygen Species; Recovery; Regimen; Regulation; Reporting; Risk; Role; Signal Transduction; Stem cell transplant; Stress; Supplementation; System; Testing; Therapeutic; Transplantation; Whole-Body Irradiation; Wild Type Mouse; Work; acquired bone marrow failure; adaptive immunity; alpha-Thalassemia; base; bone marrow failure syndrome; chemotherapy; conditioning; cytotoxic; exposed human population; genetic manipulation; genotoxicity; hematopoietic engraftment; hematopoietic stem cell niche; hematopoietic transplantation; improved; irradiation; mesenchymal stromal cell; migration; neuropeptide Y; neuroprotection; neurotransmission; novel therapeutic intervention; preconditioning; reconstitution; repaired; response; restoration; senescence; stem cell function; stem cell homeostasis; stem cell niche; stem cell survival; therapeutic target; transplant model

ABSTRACT Hematopoietic stem cell (HSC) transplantation is a therapeutic cure for hematological malignancies, metabolic disorders, and inherited and acquired bone marrow (BM) failure. However, myeloablative conditioning regimens routinely used for transplantation cause acute and long-term BM damage, leading to impaired blood and immune cell production, often causing fatal consequences. Although myeloablative irradiation/chemotherapy-induced defects in the BM microenvironment/niche have been reported, the underlying mechanism(s) are not well understood. The other crucial limiting factor for HSC transplantation is an inadequate number/quality of transplantable HSPC collected from patients or donors. Emerging evidence suggests the pivotal role of neuronal signals in the BM niche and HSC function. Peripheral neuropathy is a common complication associated with radiotherapy and chemotherapy. Thus, a deficit of neuronal signals in the BM can impair hematopoietic reconstitution. We recently reported that neuropeptide Y (NPY), one of the most abundant neurotransmitters, regulates hematopoietic stem and progenitor cell (HSPC) release into circulation by regulating BM vascular gateway function. Preliminary data showed that steady-state, NPY knockout (KO) mice have fewer HSPC and BM niche endothelial cell (EC) and mesenchymal stromal cell (MSC) than wild-type (WT) mice. Interestingly, total body irradiation (TBI) reduces NPY levels in mouse BM, accompanied by a scarcity of EC and MSC. Furthermore, we found that BM EC and MSC from NPY KO mice produce higher reactive oxygen species (ROS) than WT mice. Also, NPY supplementation enhances HSPC ex vivo expansion. Based on these observations, we hypothesize that NPY is required for BM niche regulation and HSPC homeostasis, and cytotoxic stress- induced deficit of NPY signals in the BM impairs NPY-regulated BM niche extrinsic and HSPC intrinsic mechanisms leading to hematopoietic dysfunction. This hypothesis will be tested in three aims herein: Specific aim 1 will investigate whether myeloablative irradiation-mediated deficit of NPY signals in the BM causes acute and chronic defects in the BM niche and impairs hematopoietic regeneration. Using mouse HSC transplantation models, we will evaluate the relationship between NPY signals and irradiation-induced structural and functional defects in the BM niche and HSPC. Specific aim 2 will identify the mechanism(s) via which NPY signals promote BM niche restoration and hematopoietic regeneration. We will use molecular and functional analysis to explore how NPY signals control oxidative stress and vascular integrity in the BM niche constituents. Specific aim 3 will investigate whether NPY supplementation during ex vivo HSPC expansion can improve hematopoietic engraftment after transplantation. The proposed studies will shed new light on how stress-induced neuropathy contributes to stem cell niche damage and blood stem cell defects and identify a potential therapeutic target to improve HSC transplantation.

抽象的 造血干细胞（HSC）移植是治疗血液系统恶性肿瘤、代谢性疾病的一种治疗方法。 疾病、遗传性和获得性骨髓 (BM) 衰竭。然而，清髓性预处理方案 常规用于移植会导致急性和长期的骨髓损伤，导致血液和免疫受损 细胞的产生，常常造成致命的后果。尽管清髓性放疗/化疗引起的 BM 微环境/生态位的缺陷已被报道，其潜在机制尚不明确 明白了。 HSC 移植的另一个关键限制因素是数量/质量不足 从患者或捐赠者收集的可移植 HSPC。新的证据表明神经元的关键作用 BM 生态位和 HSC 功能中的信号。周围神经病变是一种常见的并发症 放射治疗和化学治疗。因此，BM 中神经元信号的缺陷会损害造血功能 重构。我们最近报道了神经肽 Y (NPY)，最丰富的神经递质之一， 通过调节 BM 血管来调节造血干细胞和祖细胞 (HSPC) 释放到循环中 网关功能。初步数据显示，稳态 NPY 敲除 (KO) 小鼠的 HSPC 和 BM 生态位内皮细胞 (EC) 和间充质基质细胞 (MSC) 高于野生型 (WT) 小鼠。有趣的是， 全身照射 (TBI) 降低小鼠 BM 中的 NPY 水平，并伴有 EC 和 MSC 的缺乏。 此外，我们发现 NPY KO 小鼠的 BM EC 和 MSC 产生更高的活性氧 (ROS) 比 WT 小鼠。此外，补充 NPY 还可增强 HSPC 离体扩增。根据这些观察， 我们假设 NPY 是 BM 生态位调节和 HSPC 稳态以及细胞毒性应激所必需的 - BM 中 NPY 信号的诱导缺陷会损害 NPY 调节的 BM 生态位外在和 HSPC 内在 导致造血功能障碍的机制。该假设将在本文的三个目标中得到检验： 具体目标 1 将研究清髓性照射是否介导 BM 中 NPY 信号的缺陷 导致骨髓生态位的急性和慢性缺陷并损害造血再生。使用鼠标 HSC 移植模型中，我们将评估 NPY 信号与辐射诱导结构之间的关系 BM 生态位和 HSPC 的功能缺陷。 具体目标 2 将确定 NPY 信号促进 BM 生态位恢复的机制和 造血再生。我们将利用分子和功能分析来探索 NPY 信号如何控制 BM 生态位成分中的氧化应激和血管完整性。 具体目标 3 将研究在离体 HSPC 扩增过程中补充 NPY 是否可以改善 移植后的造血植入。 拟议的研究将为压力诱发的神经病变如何影响干细胞生态位提供新的线索 损伤和血液干细胞缺陷，并确定改善 HSC 移植的潜在治疗靶点。