Gadd 45 in the Response of Hematopoietic Cells to Stress

描述（由申请人提供）：Gadd 45蛋白是细胞应激反应的关键参与者。这些蛋白与细胞周期和应激反应蛋白相互作用，包括PCNA，p21，Cdc 2/cyclinB 1，MEKK 4和p38激酶。利用gadd 45缺失小鼠，已经进行了几个重要的观察。这包括gadd 45基因在调节造血细胞对遗传毒性和生理应激的反应中起重要作用的证据，包括造血细胞因子，骨髓清除剂和炎症物质的急性刺激。统一的假设是，Gadd 45蛋白是响应于遗传毒性和生理刺激的相关造血应激信号传导途径的调节剂，并且在造血级联的子区室中具有不同的作用;此外，Gadd 45功能通过与应激信号传导中涉及的伴侣蛋白结合来表现。Gadd 45 a和Gadd 45 b发挥促存活作用，保护骨髓细胞免受遗传毒性应激诱导的细胞死亡，包括紫外线辐射（UV）、VP-16和柔红霉素（DNR）。目的1旨在阐明Gadd 45蛋白通过其保护骨髓细胞免受遗传毒性应激的信号通路。获得了Gadd 45 a和Gadd 45 b响应于分化细胞因子的急性刺激而调节骨髓祖细胞的存活和分化的证据。目标2中提出的实验旨在评估Gadd 45蛋白如何与伴侣相互作用以调节用分化细胞因子急性刺激后的终末分化程序，所述分化细胞因子是模拟炎症应激期间发生的情况的条件。初步证据表明，Gadd 45 b和Gadd 45 a也调节造血干细胞（HSC）的功能。目的3将确定这些Gadd 45蛋白在调节HSC功能中起什么作用。这项研究计划应该会增加对造血细胞应激反应的理解，并为在临床相关环境中评估Gadd 45蛋白的状态对化疗药物和抗炎药物疗效的影响奠定基础。

DESCRIPTION (provided by applicant): Gadd45 proteins are key players in cellular stress responses. These proteins interact with cell cycle & stress response proteins, including PCNA, p21, Cdc2/cyclinB1, MEKK4 & p38 kinase. Taking advantage of the gadd45 null mice several important observations have been made. This includes evidence that gadd45 genes play an important role in regulating the response of hematopoietic cells to genotoxic & physiological stress, including acute stimulation by hematopoietic cytokines, myeloablating agents & inflammatory substances. The unifying hypothesis is that Gadd45 proteins are modulators of interrelated hematopoietic stress signaling pathways in response to genotoxic & physiological stimuli, and have distinct roles in sub-compartments of the hematopoietic cascade; in addition, Gadd45 functions are manifested by binding to partner proteins implicated in stress signaling. Gadd45a and Gadd45b play pro-survival roles, protecting myeloid cells from genotoxic stress induced cell death, including ultraviolet-radiation (UV), VP-16 & daunorubicin (DNR). Aim 1 is targeted at elucidating signaling pathways via which Gadd45 proteins protect myeloid cells from genotoxic stress. Evidence was obtained that Gadd45a & Gadd45b modulate survival & differentiation of myeloid progenitors in response to acute stimulation with differentiating cytokines. Experiments proposed in Aim 2 are targeted at assessing how Gadd45 proteins interact with partners to regulate the program of terminal differentiation following acute stimulation with differentiating cytokines, conditions that mimic what occurs during inflammatory stress. Preliminary evidence shows that Gadd45b and Gadd45a also modulate the function of hematopoietic stem cells (HSC). Aim 3 will determine what role(s) these Gadd45 proteins play in modulating HSC functions. This research plan should result in increased understanding of stress responses of hematopoietic cells, & set the stage to evaluate, in clinically relevant settings, the impact the status of Gadd45 proteins has on the efficacy of chemotherapeutic agents & anti inflammatory drugs.