T-cell growth factor pathways and immune modulation

T 细胞生长因子途径和免疫调节

• 批准号: 6764118
• 负责人: Robert A. Kirken
• 金额: $ 25.99万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764118
• 关键词: cell; growth; factor; pathways; immune

DESCRIPTION (provided by applicant): Organ failure associated with aging and advanced diabetes mellitus as well as severe autoimmune and inflammatory diseases represents 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 cyclosporine 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 mediated immunity, and that in addition to the Jak3 tyrosine kinase, a yet-to-be identified Stat5 serine kinase is also important 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

描述（由申请人提供）：与衰老和晚期糖尿病以及严重的自身免疫和炎症性疾病相关的器官衰竭代表着严重的医疗问题。尽管取得了重大进展，但实现有效的免疫抑制和长期移植物存活仍然是一个严重的障碍，而与这些第一代和第二代免疫抑制剂（包括环孢菌素 A 和 FK506）相关的极端副作用和毒性使情况变得更加复杂。因此，有必要探索 T 细胞激活和扩增的新分子方面，以便设计安全有效的治疗策略。尽管环孢菌素以 T 细胞受体激活为目标，但现在有多项证据证明对由白细胞介素 2 (IL2) 家族细胞因子驱动的 T 细胞活性后期阶段进行关键研究是合理的，作为免疫抑制的新分子靶点。在此应用中，我们提供了广泛且令人信服的初步数据，表明 IL2 诱导的 Stat5 磷酸化的药理学抑制对于动物模型中的同种异体移植排斥非常有效。本应用的目的是研究调节 Stat5a/b 激活的效应途径及其靶向基因。待测试的主要假设是，活性 Stat5 转录因子对于 T 细胞介导的免疫至关重要，并且除了 Jak3 酪氨酸激酶之外，尚未鉴定的 Stat5 丝氨酸激酶对于介导 T 细胞反应也很重要。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 Stat5a/b 激活的作用，2) 功能性表征和鉴定 80 kDa 脯氨酸导向的 Stat5 丝氨酸激酶； 3) 使用全基因组技术捕获 Stats 反应元件，识别人类 T 细胞中的 Stat5 靶基因。这项工作很重要，并且可能通过为可以替代或补充当前治疗的新免疫抑制策略提供直接的分子原理和临床前证据来显着推进该领域的发展