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.

摘要 造血干细胞(HSC)移植是治疗血液系统恶性肿瘤、代谢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，清髓性调节方案 常规用于移植会导致急性和长期的骨髓损伤，导致血液和免疫功能受损 细胞产生，往往会造成致命的后果。尽管清髓性放射/化疗诱导 BM微环境/生态位缺陷已有报道，其潜在机制(S)不太好 明白了。造血干细胞移植的另一个关键限制因素是移植的数量/质量不足 从患者或供者处收集的可移植HSPC。新出现的证据表明，神经元的关键作用 BM小生境和HSC中的信号起作用。周围神经病变是与以下疾病相关的常见并发症 放射治疗和化疗。因此，骨髓中神经元信号的缺失可能会损害造血。 重建。我们最近报道了神经肽Y(NPY)，一种最丰富的神经递质， 通过调节骨髓血管调节造血干/祖细胞(HSPC)释放到循环中 网关功能。初步数据显示，稳定状态的NPY基因敲除(KO)小鼠的HSPC和 BM生态位内皮细胞(EC)和间充质基质细胞(MSC)均高于野生型(WT)小鼠。有趣的是， 全身照射可降低小鼠骨髓中NPY水平，并伴有EC和MSC的缺乏。 此外，我们还发现来自NPY KO小鼠的BM EC和MSC产生更高的活性氧(ROS)。 而不是WT小鼠。此外，补充NPY可促进HSPC的体外扩增。基于这些观察， 我们假设神经肽Y是BM生态位调节和HSPC动态平衡所必需的，而细胞毒性应激- 骨髓NPY信号的诱导缺失削弱NPY调节的骨髓细胞内源性和外源性小生境 导致造血功能障碍的机制。这一假设将在本文的三个目标中得到检验： 具体目标1将调查清髓性照射是否介导骨髓中NPY信号的缺失 会导致骨髓壁龛的急性和慢性缺陷，并损害造血再生。使用鼠标HSC 移植模型，我们将评估NPY信号与辐射诱导的结构性结构的关系 以及BM和HSPC的功能缺陷。 具体目标2将确定神经肽Y信号促进骨髓生态位修复和修复的机制(S) 造血再生。我们将使用分子和功能分析来探索NPY信号是如何控制的 BM壁龛成分中的氧化应激和血管完整性。 具体目标3将调查在体外HSPC扩增过程中补充NPY是否可以改善 移植后的造血植入。 这项拟议的研究将阐明应激诱导的神经病如何对干细胞生态位做出贡献。 并确定一个潜在的治疗靶点，以改善造血干细胞移植。