T-cell growth factor pathways and immune modulation

与衰老和晚期糖尿病相关的器官衰竭以及严重的自身免疫性和 炎症性疾病是严重的医疗问题。尽管取得了重大进展，但实现了有效的 免疫抑制和移植物长期存活仍然是一个严重的障碍，这一障碍因其 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FK506。因此，探索T细胞的新的分子方面是必要的 激活和扩张，以便设计安全有效的治疗策略。鉴于 环孢素Jne靶向T细胞受体激活，几条证据现在证明了一项关键的研究 以白细胞介素2家族细胞因子为新分子靶点的T细胞晚期活性 用于免疫抑制。在本申请中，我们提供了广泛且令人信服的初步数据 提示药物抑制IL2诱导的Stat5磷酸化是非常有效的 在动物模型中抗同种异体移植排斥反应。此应用程序的目标是研究效应器 调节Stat5a/b激活及其靶向基因的通路。要检验的主要假设 激活的Stat5转录因子对T细胞修饰的免疫至关重要，而且除了 JAK3酪氨酸激酶是一种尚未鉴定的Stat5丝氨酸激酶，也是T细胞的重要介导者 回应。为了实现这项提案的目标，我们将追求三个具体目标：1)确定 早、晚期T细胞表面受体调节Stat5a/b激活的作用，2)功能 鉴定80 kDa脯氨酸诱导的Stat5丝氨酸激酶；3)鉴定Stat5靶基因 在人类T细胞中使用一种全基因组技术来捕获Stats反应元件。这项工作是 重要，并可能通过提供直接的分子基础和临床前研究而显著推动该领域的发展 一种新的免疫抑制策略可以取代或补充电流的证据 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.