Regulation of Stem Cell Aging and Cancer by the Vascular Niche

项目摘要 这份K 08提案旨在通过课程、培训和职业发展促进我的职业发展。 专业发展，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在造血方面进行了额外的训练。 干细胞生物学，以完善我在转化研究的技能，实现我的长期目标， 成为造血和白血病易感性领域的独立研究者和领导者。我 因此，短期目标是在John Chute博士的实验室进行额外的研究培训，目的是 增加对骨髓（BM）小生境在造血干细胞（HSC）中作用的理解 衰老、损伤和白血病导致的功能衰退。 随着HSC老化，它们显示出明显的异常，例如向髓样分化倾斜， 繁殖能力和癌症易感性。在临床上，这与以下疾病的发病率增加相对应： 骨髓增生异常、骨髓增生性疾病、急性白血病以及适应性免疫系统缺陷。我们 实验室已经证明，BM内皮细胞（EC）产生表皮生长因子（EGF）， 显著加速急性辐射后HSC再生和整体造血重建 损伤有趣的是，高剂量辐射在造血干细胞中产生了加速衰老的表型。 系统因此，我推测HSC血管龛旁分泌机制的增强，如 EGF信号通路可以挽救这种下降的功能。 具体的目的和方法是（1）确定EGF治疗是否足以逆转HSC 衰老，使用药理学方法，（2）确定EGFR的细胞特异性缺失是否加速 HSC和免疫系统老化，使用导致骨上EGFR功能丧失的小鼠模型 骨髓干细胞和祖细胞，（3）确定EGF逆转HSC衰老的机制 通过检测EGF对HSC衰老、存活、细胞周期状态和Ras/MEK/ERK通路的影响。 这是一个高影响力，翻译的建议，适用于国家的最先进的技术和独特的鼠标模型 EGF的作用和机制，使老化的HSC再生。这将提供一个基础 EGF的新作用，并有显着的翻译潜力，以改善HSC老化的不利影响， 以及化疗、放疗和骨髓移植后的损伤。

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.