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.

摘要 造血系统对各种压力非常敏感。放射治疗通常不会导致 不仅急性造血抑制，而且长期骨髓（BM）损伤，BM风险增加 失败或恶性肿瘤。衰老过程中损伤的积累是对HSC的另一种类型的应激。 提高HSC的存活率和维持其基因组的完整性对于HSC的保存至关重要 自我更新功能和保护免受应激诱导的BM损伤。然而， 机制没有很好的定义。目前还没有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确定新的 靶向HSC应激调节蛋白latexin的药物化合物和转录机制 (Lxn)探讨Lxn抑制对辐射损伤的保护作用及HSC再生的机制。 我们已经确定了一种新的Lxn抑制剂小化合物，并发现它通过以下方式显着增加生存率： 通过新鉴定的辐射后羧肽酶A抑制的典型机制保护HSC。 Lxn缺失还减轻了HSC的衰老相关功能下降。我们假设制药和 Lxn的转录抑制保护HSC和血液系统免受应激（辐射和老化）诱导的 通过上调经典CPA3途径导致功能下降。目的1是确定 Lxn失活通过上调典型的Lxn蛋白表达来防止辐射诱导的BM损伤的机制 CPA3途径。目的2：探讨Lxn铅抑制剂对辐射损伤的防护作用机制。 造血系统目的3是确定Lxn抑制在使老化HSC再生中的作用。发现将 推进我们对Lxn如何调节应激造血的新机制的认识。结果将提供 这是一个令人信服的起点，为通过靶向Lxn发现新药奠定了基础，这将使患者受益 以及HSC功能障碍和免疫老化老年人。