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