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: 6841172
• 负责人: Robert A. Kirken
• 金额: $ 10.99万
• 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 2005-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841172
• 关键词: cell; growth; factor; pathways; immune; cell; growth; factor; pathways; immune

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================

超过提供的空间。与衰老和晚期糖尿病以及严重的自身免疫和炎症性疾病有关的器官衰竭代表了严重的医疗问题。尽管取得了重大进展，但实现有效的免疫抑制和长期移植生存仍然是一个严重的障碍，与这些第一和第二代免疫抑制剂有关的极端副作用和毒性（包括环孢素A和FK506）变得复杂。因此，探索T细胞激活和扩展的新分子方面至关重要，以便可以设计安全有效的治疗策略。尽管环孢子虫靶向T细胞受体激活，但现在有几条证据证明了对T细胞活性后期的批判性研究是合理的，该研究由白介素2（IL2）家族细胞因子驱动，这是用于免疫抑制的新分子靶标。在此应用中，我们提出了广泛而引人注目的初步数据，这表明药理学抑制IL2诱导的STAT5磷酸化对动物模型中的同种异体移植排斥非常有效。该应用的目的是研究调节STAT5A/B激活及其靶向基因的效应途径。要测试的主要假设是，活性STAT5转录因子对于T细胞的转化免疫力至关重要，除了JAK3酪氨酸激酶外，尚未确定的STAT5丝氨酸激酶也对介导T细胞反应也是不可变化的。为了实现该提案的目标，我们将追求三个具体目标以确定早期和晚期T细胞表面受体调节STAT5A/B激活的作用，2）功能表征并识别80 kDa指导的STAT5丝氨酸激酶； 3）使用全基因组技术来捕获统计数据响应元素，鉴定人类T细胞中的STAT5靶基因。这项工作很重要，并且可以通过提供直接的分子原理和临床前证据来显着推动这一领域，从而为新的免疫抑制策略提供可能取代或补充当前治疗方法。表演站点=============================================================================================