T-cell growth factor pathways and immune modulation

T 细胞生长因子途径和免疫调节

基本信息

批准号：
7176909
负责人：
Robert A. Kirken
金额：
$ 24.56万
依托单位：
UNIVERSITY OF TEXAS EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7176909
关键词：
Adverse effects Allografting Animal Model Autoimmune Diseases Autoimmune Process Cell physiology Cell surface Cellular Immunity Complement Cyclosporine Data Diabetes Mellitus Disease Disruption Dose Elderly FK506 Family Functional disorder Gene Activation Gene Targeting Generations Genetic Genome Glucocorticoids Graft Rejection Graft Survival Health Human Immune Immunity Immunocompromised Host Immunosuppression Immunosuppressive Agents Inflammatory Interleukin 2 Receptor Interleukin-2 Investigation Kidney Lymphocyte Lymphocyte Activation Mediating Medical Molecular Molecular Target Mus Organ failure Pathogenesis Pathway interactions Pharmaceutical Preparations Phase Phosphorylation Physiological Population Positioning Attribute Proline Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Range Receptor Activation Receptor Signaling Reporting Research Response Elements Role STAT protein Serine Signal Transduction Signal Transduction Pathway Sirolimus T-Cell Activation T-Cell Immunodeficiency T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Therapeutic immunosuppression Toxic effect Transplantation Immunology Transplanted tissue Tyrosine Tyrosine Phosphorylation Work cytokine design experience immunoregulation improved insight novel novel therapeutics pre-clinical prevent prolyl-serine receptor response seryl-proline tool transcription factor

项目摘要

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.

与衰老和晚期糖尿病以及严重的自身免疫性疾病相关的器官衰竭炎症性疾病代表严重的医疗问题。尽管取得了重大进展，但取得了有效免疫抑制和长期移植物存活仍然是一个严重的障碍，而且由于它们的影响而变得更加复杂。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，有必要探索 T 细胞的新分子方面激活和扩展，以便设计安全有效的治疗策略。然而环孢菌素以 T 细胞受体激活为目标，现在有几条证据证明对环孢素进行严格研究是合理的由白细胞介素 2 (IL2) 家族细胞因子作为新分子靶标驱动的 T 细胞活动的后期阶段用于免疫抑制。在此应用程序中，我们提供了广泛且令人信服的初步数据表明药物抑制 IL2 诱导的 Stat5 磷酸化非常有效对抗动物模型中的同种异体移植排斥。此应用程序的目的是研究效应器调节 Stat5a/b 激活及其靶向基因的途径。待检验的主要假设活性 Stat5 转录因子对于 T 细胞调节的免疫至关重要，并且除了 Jak3 酪氨酸激酶（一种尚未鉴定的 Stat5 丝氨酸激酶）对于介导 T 细胞也很重要回应。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) 功能上表征并鉴定 80 kDa 脯氨酸导向的 Stat5 丝氨酸激酶； 3) 鉴定 Stat5 靶基因使用全基因组技术捕获人类 T 细胞中的 Stats 反应元件。这部作品是重要，并且可以通过提供直接的分子原理和临床前显着推进该领域有证据表明新的免疫抑制策略可以取代或补充当前的免疫抑制策略治疗。