Dissecting the relationship between declining lymphoid progenitor fitness and agi

描述（由申请方提供）：本提案将尝试表征衰老相关炎症增加和白细胞介素-7受体（IL-7 R）信号传导减少如何改变造血B细胞祖细胞群并促进费城染色体（Ph+）细胞扩增。Ph+ B细胞急性淋巴细胞白血病（B-ALL）的发病率在50岁以后显著增加。这种类型的癌症是由费城染色体的产生引起的，费城染色体在造血祖细胞群中产生组成型活性激酶（Bcr-Abl）。这种癌基因的表达导致细胞生长不受调节。虽然费城染色体的表现在所有年龄组中都有观察到，但在年轻人中很少观察到Ph+白血病。基于这一观察，本项目的目标有两个方面：1.确定信号的程度， 由增加的炎症或减少的IL-7 R介导的信号传导诱导的相对于年轻群体在老年B细胞祖细胞中发生的代谢变化;和2.确定Ph+ B-ALL的衰老相关增加是否是Bcr-Abl恢复或规避衰老B细胞祖细胞中发现的已识别信号传导或代谢缺陷的能力所致。这些研究将揭示衰老相关的炎症增加和IL-7 R介导的信号转导减少如何促进B细胞祖细胞群中的白血病发生。由于年龄已被描述为许多癌症发展中最重要的预后因素，本研究可能有助于确定连接不同病因的衰老相关癌症的共同主题，从而改善各种衰老相关恶性肿瘤的治疗方法。

DESCRIPTION (provided by applicant): This proposal will attempt to characterize how aging-associated increases in inflammation and decreased interleukin-7 receptor (IL-7R) signaling alter hematopoietic B-cell progenitor populations and promote the expansion of Philadelphia Chromosome (Ph+) cells. The incidence of Ph+ B-cell acute lymphoblastic leukemias (B-ALL) increases significantly after age 50. This type of cancer results from the generation of the Philadelphia Chromosome, which creates a constitutively active kinase (Bcr-Abl) in hematopoietic progenitor cell populations. The expression of this oncogene results in unregulated cellular growth. Although the manifestation the Philadelphia Chromosome has been observed in all age groups, Ph+ leukemias are rarely observed in young individuals. Based on this observation the goals of this project are two-fold: 1.To determine the extent of signaling and metabolic changes that occur in aged B-cell progenitors relative to young populations induced by increased inflammation or decreased IL-7R mediated signaling; and 2. To determine if the aging-associated increases in Ph+ B-ALL results from the ability of Bcr-Abl to restore or circumvent identified signaling or metabolic defects found in aged B-cell progenitors. These studies will reveal how aging-associated increases in inflammation and decreases in IL-7R mediated signaling promote leukemogenesis in B-cell progenitor populations. Since age has been described as the single most important prognostic factor in the development of many cancers, this study may help to identify common themes that connect aging-associated cancers of varying etiological origin which could lead to improved therapeutics for various aging-associated malignancies.