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

描述（由申请人提供）：所有组织都包含干细胞和祖细胞群，它们受到内在和外在线索的引导。多能胚胎干细胞产生生物体中的所有组织，而成体干细胞通过维持组织稳态来维持器官功能。衰老的特点是器官功能逐渐衰退。由于成体干细胞的主要作用是维持组织的完整性，它们不可避免地促成了这种现象。造血系统是干细胞如何改变以支持健康免疫系统的一个例子。确定调节造血干细胞（HSC）在生命不同阶段（胎儿、“年轻”成人和“年老”成人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。E3连接酶Fbw7已被证明通过调节c-Myc蛋白影响HSC自我更新。c-Myc丰度是静止的“年轻”成年hsc的标志，在分化过程中被上调。胚胎小鼠、“年轻”成年小鼠和“年老”成年小鼠的造血干细胞中c-Myc蛋白丰度不同。值得注意的是，c-Myc蛋白在“老年”成人hsc中的表达水平高于“年轻”成人hsc，这表明静止状态发生了改变。髓性白血病，如慢性髓性白血病（CML），是在造血干细胞内发生BcrAbl易位时发生的。有趣的是，CML主要发生在60岁左右的患者中，这可能意味着老年HSC是转化的来源。在本研究中，我们假设Fbw7底物相互作用维持了不同年龄组造血干细胞自我更新和分化之间的关键平衡，并且Fbw7可能是CML的治疗靶点。

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.