T-cell growth factor pathways and immune modulation

与衰老和晚期糖尿病以及严重的自身免疫性和 炎性疾病是严重的医学问题。尽管取得了重大进展， 免疫抑制和移植物长期存活仍然是一个严重的障碍， 与这些第一代和第二代免疫抑制剂相关的极端副作用和毒性 包括环孢素A和FK 506。因此，有必要探索T细胞的新的分子方面， 激活和扩展，以便可以设计安全有效的治疗策略。而 环孢霉素靶向T细胞受体活化，现在有几条证据证明了对环孢霉素的关键研究是正确的。 T细胞活性的后期阶段，由白细胞介素2（IL 2）家族细胞因子作为新的分子靶点驱动 免疫抑制在这个应用程序中，我们提出了广泛的和令人信服的初步数据 表明IL 2诱导的Stat 5磷酸化的药理学抑制显著有效 在动物模型中对抗同种异体移植排斥反应。本申请的目的是研究效应器 调节Stat 5a/B激活的途径及其靶基因。待检验的主要假设 活化的Stat 5转录因子对于T细胞修饰的免疫是关键的，并且除了 Jak 3酪氨酸激酶是一种尚未鉴定的Stat 5丝氨酸激酶，也是介导T细胞增殖的重要分子。 应答为了实现本提案的目标，我们将追求三个具体目标：1）确定 早期和晚期T细胞表面受体调节Stat 5 a/B活化作用，2）功能上 表征和鉴定80 kDa脯氨酸导向的Stat 5丝氨酸激酶;和3）鉴定Stat 5靶基因 在人类T细胞中使用全基因组技术捕获Stats反应元件。这项工作是 重要的是，并可能通过提供直接的分子理论基础和临床前 新的免疫抑制策略的证据，可以取代或补充目前的 治疗。

Organ failure associated with aging and advanced diabetes mellitus as well as severe autoimmune and inflammatory diseases represent severe medical problems. Despite major progress, achieving effective immunosuppression and long-term graft survival remains a serious obstacle that is complicated by their extreme side effects and toxicities associated with these first and second generation immunosuppressants including cyclosporine A and FK506. It is therefore essential to explore novel molecular aspects of T-cell activation and expansion so that safe and effective therapeutic strategies can be designed. Whereas cyclosporJne targets T-cell receptor activation, several lines of evidence now justify a critical investigation of the later phase of T cell activity that is driven by interleukin-2 (IL2) family cytokines as new molecular targets for immune suppression. In this application, we present extensive and compelling preliminary data suggesting that pharmacological inhibition of IL2-induced Stat5 phosphorylation is remarkably effective against allograft rejection in animal models. The objective of this application is to investigate the effector pathways that regulate Stat5a/b activation and the genes they target. The principal hypothesis to be tested is that active Stat5 transcription factors are critical for T cell modiated immunity, and that in addition to the Jak3 tyrosine kinase, a yet-to-be identified Stat5 serine kinase is also imporotant for mediating T cell responses. To accomplish the objective of this proposal, we will pursue three specific aims to 1) Determine the role that early and late phase T-cell surface receptors regulate Stat5a/b activation, 2) Functionally characterize and identify the 80 kDa proline-directed Stat5 serine kinase; and 3) Identify Stat5 target genes in human T cells using a genome-wide technology for trapping Stats response elements. This work is important, and may significantly advance the field by providing direct molecular rationale and preclinical evidence for a new immunosuppressive strategy that could replace or complement current treatments.