HETEROCHROMATIN RECRUITMENT OF THE VPAC1 LOCUS BY IKAROS

这项建议的重点是研究控制伊卡洛斯介导的分子机制。 T淋巴细胞血管活性肠肽受体-1的转录调控 Ikaros是淋巴生成的主要调节者，并为T细胞激活设定阈值。伊卡洛斯变异了 小鼠模型发生侵袭性淋巴母细胞白血病，发病率为100%。一些人类 白血病表达突变的显性阴性Ikaros亚型，抑制全长Ikaros DNA结合。 Ikaros DNA结合力下降可能下调一组能够调节T细胞的基因 细胞增殖。最近，我们证明了VPACR-1基因是一种偶联的G蛋白，具有抗病毒作用。 Nah Have CD4T细胞上表达的增殖受体，是Ikaros的一个新的基因靶点。信令通过 抗增殖的VPACR-1受体可能会自然地阻碍CD4T细胞进入细胞周期。因此， 在某些淋巴母细胞性疾病中，伊卡洛斯蛋白和/或DNA结合能力降低 白血病，可能下调VPACR-1，并导致不受控制的增殖。了解如何 Ikaros调节天然和活化的CD4T细胞中的VPACR-1。)提供对至关重要的 Ikaros下游事件，导致造血系统疾病中的不受控制的增殖 和2.)了解Ikaros介导的VPACR-1在正常人群中的调节作用 免疫功能，如抑制某些器官中旁观者T细胞的激活，包括 胃肠道系统。因此，本研究的目的是：1)确认的双向效果 Ikaros对原始和活化的CD4T淋巴细胞VPACR-1表达的影响，2.示范 哪些PKC通路信号蛋白介导TCR依赖的VPACR-1下调，以及3. 鉴定在T细胞中介导IK向异染色质募集的IK磷受体残基 激活。

The focus of this proposal is to investigate the molecular mechanisms governing Ikaros-mediated transcriptional regulation of vasoactive intestinal peptide receptor - 1 (VPACR-1) in T lymphocytes. Ikaros is a master regulator of lymphopoiesis and sets the threshold for T cell activation. Ikaros mutated mouse models develop an aggressive lymphoblastic leukemia with 100% incidence. Some human leukemias express mutated dominant negative Ikaros isoforms that inhibit full-length Ikaros DNA binding. Decreases in Ikaros DNA binding capacity may downregulate a subset of genes capable of regulating T cell proliferation. Recently, we demonstrated that the gene for VPACR-1, a G protein coupled, anti- proliferative receptor expressed on nah've CD4 T cells, is a novel gene target for Ikaros. Signaling through the anti-proliferative VPACR-1 receptor may naturally impede cell cycle entry in CD4 T cells. Therefore, a decrease in Ikaros protein and/or DNA binding capacity, during certain etiologies of lymphoblastic leukemia, may downregulate VPACR-1 and contribute to uncontrolled proliferation. Understanding how Ikaros regulates VPACR-1 in na'fve and activated CD4T cells may 1.) provide insight into a crucial downstream event from Ikaros that contributes to uncontrolled proliferation in hematopoietic disorders and 2.) lead to an understanding of the role Ikaros-mediated regulation of VPACR-1 plays in normal immune function, such as suppressing bystander T cell activation in certain organs including the gastrointestinal system. Therefore, the aims of this research are to 1.) confirm bi-directional effects of Ikaros on VPACR-1 expression in primary naive and activated CD4 T lymphocytes, 2.) demonstrate which PKC pathway signaling proteins mediate TCR-dependent VPACR-1 downregulation, and 3.) identify IK phosphoacceptor residues that mediate IK recruitment to heterochromatin during T cell activation.