IL-7 and Lymphocyte Homeostasis: Life versus Death

描述(由申请人提供)：免疫系统的动态平衡是通过支持生命和支持死亡的信号之间的平衡来维持的，并可获得细胞因子白介素7(IL-7)，这是限制种群数量的关键资源。细胞死亡是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来调节的。通过探索IL-7的这些生物活性，这一建议扩大了对癌症起源的理解。来自拟议研究的关键发现将被开发成一个创新的研究计划，旨在研究IL-7在淋巴增生症中的作用。需要检验的假设是，IL-7通过抑制bcl2家族的凋亡蛋白促进生命，同时通过磷酸酶CDc25A调节细胞周期，并通过葡萄糖摄取维持代谢资源。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bcl2的效应活性。这将通过检测淋巴细胞中BIM的活性来确定--IL-7如何调节BIM，以及BIM如何与其他bcl-2家族成员相互作用。IL-7作为一种增殖因子的活性将通过检测细胞周期的关键介质--磷酸酶CDC25A的调节和功能来研究。为了确定CDc25A的动态平衡潜力，将评估表达活跃、稳定形式的CDc25A的细胞在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通过维持能量来源而得到支持。通过IL-7信号调节葡萄糖摄取的因素将在抑制细胞凋亡或诱导细胞分裂的细胞中进行检测。所提出的方法将建立生理相关性的小鼠实验与使用细胞系的功能分析相结合，以检查对外周细胞内稳态至关重要的IL-7活动的潜在机制。预期的结果将对细胞因子研究领域产生重大影响。

DESCRIPTION (provided by applicant): 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.