Dissecting the relationship between declining lymphoid progenitor fitness and agi

剖析淋巴祖细胞适应性下降与敏捷之间的关系

• 批准号: 8541771
• 负责人: Curtis James Henry
• 金额: $ 8.83万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-07 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541771
• 关键词: Affect; Age; Aging; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Lymphocytes; Biological Assay; Bone Marrow Transplantation; Cell Proliferation; Cells; Chronic; Consumption; Defect; Development; Elderly; Epigenetic Process; Event; Exhibits; Gene Expression; Generations; Genes; Goals; Hematopoietic; Hematopoietic stem cells; Human; Incidence; Individual; Inflammation; Interleukin 7 Receptor; Interleukin-7; Lead; Lymphoid; Lymphopoiesis; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Microarray Analysis; Mitochondria; Mus; Mutation; NADH; Older Population; Oncogenes; Oncogenic; Pathway interactions; Philadelphia Chromosome; Phosphotransferases; Population; Production; Prognostic Factor; Receptor Signaling; Relative (related person); Research Design; Signal Transduction; Stem cells; Therapeutic; Time; age group; aged; base; cancer initiation; cancer type; cell growth; fitness; functional decline; improved; leukemia; leukemogenesis; metabolomics; mouse model; progenitor; receptor; receptor-mediated signaling; research study; stem; tumor progression

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.

描述（由申请人提供）：该提案将试图描述与衰老相关的炎症增加和白介素 7 受体 (IL-7R) 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+) 细胞的扩增。 Ph+ B 细胞急性淋巴细胞白血病 (B-ALL) 的发病率在 50 岁后显着增加。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一种组成型活性激酶 (Bcr-Abl) 。该癌基因的表达导致细胞生长失控。虽然费城染色体的表现在所有年龄组中都观察到，但Ph+白血病很少在年轻人中观察到。基于这一观察，该项目的目标有两个： 1. 确定信号传导的程度和 由于炎症增加或 IL-7R 介导的信号传导减少而导致老年 B 细胞祖细胞相对于年轻细胞群发生代谢变化； 2. 确定与衰老相关的 Ph+ B-ALL 增加是否是由于 Bcr-Abl 恢复或规避衰老 B 细胞祖细胞中已识别的信号传导或代谢缺陷的能力所致。这些研究将揭示与衰老相关的炎症增加和 IL-7R 介导的信号传导减少如何促进 B 细胞祖细胞群中的白血病发生。由于年龄被描述为许多癌症发展中最重要的预后因素，因此这项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，从而改进各种衰老相关恶性肿瘤的治疗方法。