Regulation of Hematopoietic Stem Cell Aging by the E3 ubiquitin Ligase Fbw7

描述(申请人提供)：所有组织都含有干细胞和祖细胞群体，由内在和外在线索引导。多能胚胎干细胞在生物体中产生所有组织，而成年干细胞通过维持组织内环境平衡来维持器官功能。衰老的特征是器官功能逐渐下降。由于成体干细胞的主要作用是维持组织的完整性，它们不可避免地导致了这一现象。造血系统是干细胞如何改变以支持健康的免疫系统度过一生的一个例子。识别在不同生命阶段(胎儿、“年轻”成人和“老年”成人)调节造血干细胞(HSC)自我更新和分化的信号通路将有助于阐明调节器官/组织功能的途径。研究表明，E3连接酶Fbw7通过调节c-Myc蛋白影响HSC的自我更新。C-Myc丰度是静止的“年轻”成年HSCs的一个标志，在分化过程中上调。C-Myc蛋白丰度在胎鼠、幼年成年鼠和老年成年鼠的HSC中不同。值得注意的是，与年轻的成年HSCs相比，c-Myc蛋白在“老年”成年HSCs中的表达水平更高，这表明改变了静止状态。当BcrAbl易位发生在造血干细胞中时，就会发生髓系白血病，如慢性粒细胞白血病(CML)。有趣的是，慢性粒细胞白血病主要发生在60岁以上的患者，这可能意味着老年的HSC是转化的来源。在这个建议中，我们假设Fbw7底物的相互作用在不同年龄组的HSCs的自我更新和分化之间保持着关键的平衡，并且Fbw7是CML的假定治疗靶点。 公共卫生相关性：拟议的研究在衰老和血液相关恶性肿瘤领域都具有重要意义。这项工作旨在确定在不同年龄段的小鼠中调节造血干细胞功能的重要途径。这项工作还将解决这些途径如何影响与年龄相关的疾病，如慢性粒细胞白血病。

DESCRIPTION (provided by applicant): All tissues contain stem and progenitor cell populations, which are guided by intrinsic and extrinsic cues. Pluripotent embryonic stem cells generate all tissues in an organism while adult stem cells work to sustain organ function by maintaining tissue homeostasis. Aging is characterized by a gradual decline in organ function. Since a primary role of adult stem cells is to sustain tissue integrity, they inevitably contribute to this phenomenon. The hematopoietic system is one example of how a stem cell changes to support a healthy immune system through life. Identifying signaling pathways that regulate hematopoietic stem cell (HSC) self-renewal and differentiation at different stages of life (fetal, "young" adult, and "old" adult HSCs) will shed light on pathways that regulate organ/tissue function. The E3 ligase, Fbw7, has been shown to influence HSC self-renewal through the regulation of c-Myc protein. c-Myc abundance was a hallmark of quiescent "young" adult HSCs and was up-regulated during differentiation. c-Myc protein abundance differed in HSCs from fetal, "young" adult" and "old" adult mice. Notably, c-Myc protein was expressed at higher levels in "old" adult HSCs when compared to "young" adult counterparts, suggesting an altered quiescent status. Myeloid leukemias, such as chronic myelogenous leukemia (CML), arise when a BcrAbl translocation occurs within HSCs. Interestingly, CML predominately arises in patients that are >60 years of age, possibly implicating an aged HSC as the source of transformation. In this proposal, we hypothesize that Fbw7 substrate interactions maintain a critical balance between self-renewal and differentiation in HSCs from different age groups and that Fbw7 is a putative therapeutic target in CML. PUBLIC HEALTH RELEVANCE: The research proposed has significant implications in both the field of aging and blood related malignancies. This work is intended to identify important pathways that regulate hematopoietic stem cell function in mice of different age groups. This work will also address how these pathways may impact age related diseases such as chronic myelogenous leukemia.