Mechanisms of Endothelial-dependent Hematopoietic Stem Cell Regeneration

内皮依赖性造血干细胞再生机制

• 批准号: 9330230
• 负责人: Derek Zachman
• 金额: $ 4.51万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330230
• 关键词: Acute; Address; Aging; Allogenic; Alpha Cell; Biological Assay; Blast Cell; Blood; Bone Marrow; Cell Aging; Cell physiology; Cells; Chronic; DNA Damage; DNA Repair; DNA Repair Pathway; Data; Development; Disasters; Disease; Dose; Endothelial Cells; Failure; Functional disorder; Goals; HGF gene; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Homeostasis; In Vitro; Individual; Infusion procedures; Injury; Ionizing radiation; Laboratories; Life; Measures; Mediating; Mediator of activation protein; Mus; Natural regeneration; Nuclear; Outcome; Oxidative Stress; Pancytopenia; Pathway interactions; Patients; Phenotype; Physiological; Process; Public Health; Radiation; Radiation Injuries; Radiation exposure; Radiation induced damage; Recovery; Research; Research Proposals; Risk; Signal Transduction; Solid; Source; Stress; Supporting Cell; Survivors; Technology; Testing; Tissues; Transplantation; Venous; Work; base; cell injury; cell type; chemotherapy; curative treatments; cytokine; design; differential expression; epidemiologic data; experimental study; functional outcomes; improved; improved outcome; in vivo; irradiation; leukemia; next generation; novel therapeutics; overexpression; public health relevance; radiation mitigator; repaired; response; self-renewal; senescence; tissue regeneration; transcriptome sequencing

DESCRIPTION (provided by applicant): The hematopoietic system is one of the most sensitive tissues in the body to the effects of ionizing radiation and chemotherapy. Acute hematopoietic stem cell (HSC) injury results in the suppression of hematopoiesis and predisposes to the development of hematologic disorders, including leukemia. Therefore, research endeavors aimed at regenerating HSCs have the potential to significantly improve outcomes following radiation exposure. HSCs reside in functional niches within the bone marrow, where their self-renewal and differentiation are modulated by cells that comprise the hematopoietic microenvironment. Endothelial cells (ECs) are a critical component of this microenvironment, and we have previously shown that ECs are capable of mitigating HSC- lethal doses of radiation. Our recent data indicate that ECs both regenerate HSCs and enhance DNA repair; however, the EC-derived signals responsible are not known. The goal of this proposal is to understand how ECs promote the regeneration and repair of HSCs after irradiation. To accomplish this, I will 1) determine the extent to which EC-mediated hematopoietic regeneration mitigates long-term HSC damage and dysfunction; and 2) identify EC-derived factors that promote the regeneration of radiation-damaged HSCs. Taken together, the results from these experiments will improve our mechanistic understanding of HSC regeneration and provide novel therapeutic options for enhancing hematopoietic recovery after radiation injury.

描述（由申请人提供）：造血系统是体内对电离辐射和化疗效应最敏感的组织之一。急性造血干细胞（HSC）损伤导致造血抑制并易于发展血液学病症，包括白血病。因此，旨在再生HSC的研究努力有可能显着改善辐射暴露后的结果。HSC位于骨髓内的功能小生境中，其中它们的自我更新和分化由构成造血微环境的细胞调节。内皮细胞（EC）是这种微环境的关键组成部分，我们以前已经表明，EC能够减轻HSC-致死剂量的辐射。我们最近的数据表明，内皮细胞既再生HSC，又增强DNA修复;然而，负责的内皮细胞来源的信号尚不清楚。本提案的目标是了解EC如何促进照射后HSC的再生和修复。为了实现这一点，我将1）确定EC介导的造血再生减轻长期HSC损伤和功能障碍的程度; 2）鉴定促进辐射损伤的HSC再生的EC衍生因子。总之，这些实验的结果将提高我们对HSC再生机制的理解，并为增强辐射损伤后的造血恢复提供新的治疗选择。