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和晚期糖尿病相关的器官衰竭炎症性疾病代表严重的医学问题。尽管取得了重大进展，但实现有效免疫抑制和长期移植生存仍然是一个严重的障碍，它们的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，必须探索T细胞的新分子方面激活和扩展，以便可以设计安全有效的治疗策略。然而环孢子虫靶向T细胞受体激活，现在有几条证据证明了对由白介素-2（IL2）家族细胞因子驱动的T细胞活性的后期，作为新的分子靶标用于免疫抑制。在此应用程序中，我们提供广泛而引人注目的初步数据表明药理学抑制IL2诱导的STAT5磷酸化非常有效反对动物模型中的同种异移植排斥。该应用的目的是调查效应器调节STAT5A/B激活及其靶向基因的途径。要测试的主要假设是否有活性的STAT5转录因子对于T细胞转化的免疫力至关重要，除了 JAK3酪氨酸激酶，尚未确定的STAT5丝氨酸激酶也是介导T细胞的知名度回答。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）识别STAT5靶基因在人类T细胞中，使用全基因组技术来捕获统计数据响应元素。这项工作是重要的可以取代或补充电流的新免疫抑制策略的证据治疗。