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: 10837423
• 负责人: Ying Liang
• 金额: $ 42.7万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10837423
• 关键词: Acute; Aging; Amino Acids; Angiotensin II; BCL2 gene; Binding; Binding Proteins; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Bone marrow failure; Cancer Patient; Carboxypeptidase; Carboxypeptidase A; Cellular Stress; Development; Dose; Elderly; Fluorouracil; Funding; Genes; Genetic; Genetic Transcription; Goals; HMGB2 gene; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hemorrhage; Homing; Immune; In Vitro; Induction of Apoptosis; Infection; Injury; Intervention; Knockout Mice; Knowledge; Lead; Legal patent; Life; Lymphoid; Maintenance; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Molecular; Mus; Myelogenous; Myelosuppression; NF-kappa B; Natural regeneration; Output; PC3.1 antigen; Pathologic; Pathway interactions; Patients; Pharmacologic Substance; Pharmacy (field); Physiological; Population; Process; Proliferating; Protein Subunits; Quality of life; Radiation; Radiation Protection; Radiation therapy; Regenerative capacity; Regulation; Regulator Genes; Rejuvenation; Reporting; Ribosomal Proteins; Risk; Role; Signal Transduction; Stress; System; Therapeutic; Time; Transplantation; Up-Regulation; Work; cancer therapy; cell injury; cell regeneration; drug discovery; effective therapy; functional decline; genetic regulatory protein; genome integrity; hematopoietic stem cell aging; hematopoietic stem cell self-renewal; in vivo; inhibitor; irradiation; knock-down; novel; novel therapeutics; overexpression; preconditioning; preservation; prevent; radiation mitigation; radiation response; self-renewal; senescence; stem cell survival; stem cells

ABSTRACT The hematopoietic system is very sensitive to a variety of stresses. Radiation therapy commonly results in not only acute hematopoietic suppression but also long-term bone marrow (BM) injury with increased risk of BM failure or malignancy. Accumulation of damages during aging process is another type of stress on HSCs. Enhancing HSC survival and maintaining their genomic integrity upon stress are crucial for preservation of HSC self-renewal function and for protection against stress-induced BM injury. However, the underlying molecular mechanisms are not well defined. No effective treatment has been developed to prevent or treat stress-induced HSC damages and related pathological consequences. The primary goal of this project is to identify novel pharmaceutical compounds and transcriptional mechanism that target a HSC stress regulatory protein, latexin (Lxn), and to uncover the mechanisms that Lxn suppression results in radiation protection and HSC rejuvenation. We have identified a novel Lxn inhibitor small compound and found that it significantly increases survival by protecting HSCs via a newly identified canonical mechanism of carboxypeptidase A inhibition upon radiation. Lxn deletion also mitigates aging-related functional decline of HSCs. We hypothesize that pharmaceutical and transcriptional suppression of Lxn protects HSCs and blood system from stress (radiation and aging)-induced functional decline via the upregulation of canonical CPA3 pathway. Aim 1 is to determine the molecular mechanisms by which Lxn inactivation protects against radiation-induced BM injury via up-regulation of canonical CPA3 pathway. Aim 2 is to identify the mechanism of action of Lxn lead inhibitor in radiation protection of hematopoietic system. Aim 3 is to define the role of Lxn suppression in rejuvenating old HSCs. Findings will advance our knowledge of novel mechanisms how Lxn regulates stress hematopoiesis. Results will provide a compelling starting point and lay grounds for the novel drug discovery by targeting Lxn, which will benefit patients subject to radiation treatment and old people with dysfunctional HSC and immune aging.

抽象的 造血系统对各种压力非常敏感。放射治疗通常不会导致 不仅是急性造血抑制，而且是长期骨髓 (BM) 损伤，且 BM 风险增加 失败或恶性肿瘤。衰老过程中损伤的累积是造血干细胞面临的另一种压力。 提高 HSC 的存活率并在应激时保持其基因组完整性对于 HSC 的保存至关重要 自我更新功能并防止应激引起的骨髓损伤。然而，底层分子 机制尚未明确。尚未开发出有效的治疗方法来预防或治疗压力引起的 HSC 损伤和相关病理后果。该项目的主要目标是识别新颖的 针对 HSC 应激调节蛋白乳胶蛋白的药物化合物和转录机制 (Lxn)，并揭示 Lxn 抑制导致辐射防护和 HSC 再生的机制。 我们已经鉴定出一种新型 Lxn 抑制剂小化合物，并发现它可以通过以下方式显着提高生存率： 通过新发现的羧肽酶 A 辐射抑制经典机制来保护 HSC。 Lxn 缺失还可以减轻 HSC 与衰老相关的功能衰退。我们假设制药和 Lxn 转录抑制可保护 HSC 和血液系统免受应激（辐射和衰老）诱导的影响 通过经典 CPA3 通路的上调导致功能下降。目标 1 是确定分子 Lxn 失活通过上调规范来防止辐射引起的 BM 损伤的机制 CPA3 途径。目标 2 是确定 Lxn 铅抑制剂在辐射防护中的作用机制 造血系统。目标 3 是明确 Lxn 抑制在使旧的 HSC 恢复活力中的作用。调查结果将 增进我们对 Lxn 如何调节应激造血的新机制的了解。结果将提供 令人信服的起点，为通过靶向 Lxn 的新药发现奠定基础，这将使患者受益 接受放射治疗的人和患有 HSC 功能障碍和免疫老化的老年人。

项目成果

Aged murine hematopoietic stem cells drive aging-associated immune remodeling.

衰老的小鼠造血干细胞驱动与衰老相关的免疫重塑。

• 发表时间: 2018-08-09
• 影响因子: 20.3
• 作者: Leins, Hanna;Mulaw, Medhanie;Eiwen, Karina;Sakk, Vadim;Liang, Ying;Denkinger, Michael;Geiger, Hartmut;Schirmbeck, Reinhold
• 通讯作者: Schirmbeck, Reinhold