IL-7 and Lymphocyte Homeostasis: Life versus Death

免疫系统的动态平衡是通过支持生命和支持死亡信号的平衡来维持的， 细胞因子白介素7(IL-7)的可获得性，这是限制种群数量的关键资源。细胞死亡是一种 消除健康组织中异常细胞的必要过程。细胞生长是通过调节 细胞的生命周期和代谢。通过探索IL-7的这些生物活性，这一建议扩展了 对癌症起源的理解。拟议研究的主要发现将发展成一种 旨在研究IL-7在淋巴肿瘤发生中的作用的创新研究计划。假设是 测试表明，IL-7通过抑制bcl2家族的凋亡蛋白来促进生命，同时调节细胞 循环通过磷酸酶，CDC25A，并通过葡萄糖摄取来维持代谢资源。 IL-7的丢失触发了凋亡蛋白Bax，而Bax则被bcl2抑制。研究表明， 凋亡蛋白BIM可能是IL-7信号转导的靶点，并调节Bax和Bax的效应活性 BCL-2。这将通过检测淋巴细胞中BIM的活性-IL-7如何调节BIM来确定 以及BIM如何与其他BCL-2家族成员相互作用。IL-7作为增殖因子的活性将是 通过研究细胞周期的关键介质--磷酸酶CDC25A的调节和功能来进行研究。 为了建立CDc25A的动态平衡潜力，表达活跃、稳定形式的CDc25A的细胞将被 评估在IL-7缺乏的环境中的生长情况。IL-7的存活和增殖活性可能是 以维护能源资源为支撑。IL-7介导葡萄糖摄取的因素 信号将在已抑制细胞凋亡或诱导细胞分裂的细胞中进行检测。这个 所提出的方法结合了小鼠实验的使用，这些实验建立了与 使用细胞系的功能分析来检查IL-7活性的潜在机制 外周细胞动态平衡。预期的结果将对细胞因子研究领域产生重大影响。

Homeostasis of the immune system is maintained through a balance of pro-life and pro-death signals, with availability of the cytokine, interleukin-7 (IL-7), a critical resource limiting population size. Cell death is a necessary process that eliminates abnormal cells in healthy tissue. Cell growth is mediated by regulation of the cell life cycle and metabolism. By exploring these biological activities of IL-7, this proposal expands the understanding of the origins of cancer. Key findings from the proposed studies will be developed into an innovative research program designed to study the role of IL-7 in lymphomagenesis. The hypothesis to be tested is that IL-7 promotes life by repressing apoptotic proteins of the BCL-2 family, while regulating cell cycling through the phosphatase, Cdc25A, and maintaining metabolic resources through glucose uptake. Loss of IL-7 triggers the apoptotic protein, BAX, which is inhibited by BCL-2. Studies suggest that the apoptotic protein, BIM, could be a target of IL-7 signaling and modulate the effector activities of BAX and BCL-2. This will be determined by examining the activity of BIM in lymphocytes - how IL-7 regulates BIM and how BIM interacts with other BCL-2 family members. The activity of IL-7 as a proliferative factor will be studied by examining the regulation and function of the phosphatase, Cdc25A, a key mediator of cell cycling. To establish the homeostatic potential of Cdc25A, cells expressing an active, stable form of Cdc25A will be evaluated for growth in an IL-7 deficient environment. The survival and proliferative activities of IL-7 may be supported by maintenance of energy resources. The factors mediating glucose uptake through IL-7 signaling will be examined in cells in which apoptosis has been inhibited or cell division induced. The approaches proposed combine the use of mouse experiments that establish physiological relevance with functional assays using cell lines to examine mechanisms underlying the activities of IL-7 essential for the homeostasis of peripheral cells. Expected findings will have significant impact in field of cytokine research.