Regulation of Stem Cell Aging and Cancer by the Vascular Niche

血管生态位对干细胞衰老和癌症的调节

• 批准号: 9371788
• 负责人: Vivian Y-J Chang
• 金额: $ 17.82万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371788
• 关键词: Acute; Acute leukemia; Adaptive Immune System; Address; Adverse effects; Advisory Committees; Aging; Alpha Cell; Area; Biological Assay; Blood Vessels; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; Catalogs; Cell Aging; Cell Cycle; Cell physiology; Cells; Cellular biology; Clinical; Data; Defect; Development; Dose; Dysmyelopoietic Syndromes; Endothelial Cells; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Genetically Engineered Mouse; Genomics; Goals; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Human; Immune system; Incidence; Injury; Laboratories; Light; Lymphoid; Malignant Neoplasms; Measures; Mentors; Molecular; Mus; Myelogenous; Myeloproliferative disease; Myelosuppression; Natural regeneration; Organ; Pathway interactions; Pharmacology; Phenotype; Predisposition; Radiation; Radiation Injuries; Radiation Toxicity; Radiation exposure; Radiation induced damage; Radiation therapy; Regulation; Rejuvenation; Research Personnel; Research Training; Role; Signal Pathway; Signal Transduction; Stem cells; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Effect; Training; Translational Research; Translations; Treatment Factor; Whole-Body Irradiation; aged; base; career development; cell age; cell injury; chemotherapy; experimental study; functional decline; gain of function; immune function; improved; in vivo; irradiation; leukemia; leukemogenesis; loss of function; mouse model; mutant; novel; paracrine; premature; progenitor; radiation effect; reconstitution; self-renewal; senescence; skills

Project Summary This K08 proposal has been developed to facilitate my career development through coursework, training in professional development, guidance from my mentor as well as my advisory committee, and research training. My background in genomics and cancer susceptibility has led me to pursue additional training in hematopoietic stem cell biology in order to round out my skills in translational research and achieve my long-term goal of becoming an independent investigator and leader in the area of hematopoiesis and leukemia susceptibility. My short-term goal is therefore to pursue additional research training in Dr. John Chute's lab with the aim of increasing understanding of the role of the bone marrow (BM) niche in the hematopoietic stem cell (HSC) functional decline with aging, injury, and leukemogenesis. As HSCs age, they display distinct abnormalities such as skewing toward myeloid differentiation, decreased repopulation ability, and cancer predisposition. Clinically, this corresponds with the increasing incidence of myelodysplasia, myeloproliferative diseases, acute leukemia, as well as adaptive immune system defects. Our lab has demonstrated that BM endothelial cells (ECs) produce epidermal growth factor (EGF) which is capable of markedly accelerating HSC regeneration and overall hematopoietic reconstitution following acute radiation injury. Interestingly, high dose irradiation produced a phenotype of accelerated aging in the hematopoietic system. Therefore, I hypothesize that augmentation of the HSC vascular niche paracrine mechanisms, such as the EGF signaling pathway, can rescue this declining function. The specific aims and approaches are to (1) determine whether EGF treatment is sufficient to reverse HSC aging, using pharmacologic approaches, (2) determine whether cell-specific deletion of EGFR accelerates HSC and immune system aging, using a mouse model which results in a loss-of-function of EGFR on bone marrow stem and progenitor cells, and (3) determine the mechanisms through which EGF reverses HSC aging by testing the effect of EGF on HSC senescence, survival, cell cycle status, and the Ras/MEK/ERK pathway. This is a high-impact, translational proposal that applies state-of-the-art techniques and unique mouse models to characterize the role and mechanism by which EGF rejuvenates aging HSCs. This will provide the basis of a novel role for EGF and has significant translational potential to ameliorate the adverse effects of HSC aging and injury after chemotherapy, radiation therapy, and bone marrow transplantation.

项目摘要 这项K08提案是为了通过课程，培训来促进我的职业发展的开发 专业发展，我的导师和咨询委员会的指导以及研究培训。 我在基因组学和癌症易感性方面的背景使我接受了造血的其他培训 干细胞生物学，以完善我在翻译研究方面的技能并实现我的长期目标 成为造血和白血病敏感性领域的独立研究者和领导者。我的 因此，短期目标是在John Chute的实验室中进行其他研究培训，目的 越来越了解骨髓（BM）小裂在造血干细胞（HSC）中的作用 衰老，损伤和白血病的功能下降。 随着HSC的年龄，它们表现出明显的异常，例如偏向髓样分化，减少 重生能力和癌症易感性。临床上，这与增加的发生率相对应 骨髓增生，骨髓增生性疾病，急性白血病以及自适应免疫系统缺陷。我们的 实验室已经证明BM内皮细胞（ECS）产生表皮生长因子（EGF） 急性辐射后明显加速HSC再生和整体造血重构 受伤。有趣的是，高剂量辐照产生了造血性衰老的表型 系统。因此，我假设HSC血管壁分泌机制的增强，例如 EGF信号通路可以挽救此功能下降的功能。 具体目的和方法是（1）确定EGF治疗是否足以逆转HSC 衰老，使用药理方法，（2）确定EGFR的细胞特异性缺失是否加速 HSC和免疫系统老化，使用小鼠模型，该模型导致EGFR在骨上的功能丧失 骨髓茎和祖细胞，（3）确定EGF逆转HSC衰老的机制 通过测试EGF对HSC衰老，生存，细胞周期状态和RAS/MEK/ERK途径的影响。 这是一项高影响的转化建议，应用了最先进的技术和独特的鼠标模型 表征EGF恢复衰老HSC的作用和机制。这将提供一个 EGF的新作用，具有改善HSC衰老的不利影响的显着翻译潜力 化学疗法，放射治疗和骨髓移植后的损伤。