Gadd 45 in the Response of Hematopoietic Cells to Stress

描述（由申请人提供）：Gadd45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、Cdc2/cyclinB1、MEKK4和p38激酶。利用gadd45缺失小鼠进行了几个重要的观察。这包括有证据表明gadd45基因在调节造血细胞对遗传毒性和生理应激的反应中发挥重要作用，包括造血细胞因子、清髓剂和炎症物质的急性刺激。统一的假设是Gadd45蛋白是相关的造血应激信号通路的调节剂，以响应遗传毒性和生理刺激，并在造血级联的子室中具有不同的作用；此外，Gadd45的功能通过与应激信号相关的伴侣蛋白结合而表现出来。Gadd45a和Gadd45b发挥促生存作用，保护髓细胞免受基因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Gadd45蛋白保护髓细胞免受基因毒性应激的信号通路。有证据表明，Gadd45a和Gadd45b在分化细胞因子的急性刺激下调节髓系祖细胞的存活和分化。Aim 2中提出的实验旨在评估Gadd45蛋白如何与伴侣相互作用，以调节分化细胞因子急性刺激后的终端分化程序，这种情况类似于炎症应激期间发生的情况。初步证据表明，Gadd45b和Gadd45a也能调节造血干细胞（HSC）的功能。目的3将确定这些Gadd45蛋白在调节HSC功能中起什么作用。该研究计划将增加对造血细胞应激反应的了解，并为在临床相关环境下评估Gadd45蛋白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.