T Lymphocyte Dysfunction in Lupus Erythematosus

红斑狼疮 T 淋巴细胞功能障碍

• 批准号: 6573946
• 负责人: GARY M KAMMER
• 金额: $ 39.41万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6573946
• 关键词: T lymphocyte; cellular pathology; enzyme activity; family genetics; gene mutation; genetic translation; human genetic material tag; human subject; isozymes; patient oriented research; protein kinase A; proteolysis; systemic lupus erythematosus; tissue /cell culture; ubiquitin

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by impaired T cell effector functions. We have demonstrated impaired protein kinase A-catalyzed protein phosphorylation due to deficient type I protein kinase A (PKA-I) isozyme activity. Deficient isozyme activity predominantly reflects markedly reduced or absent type I regulatory beta subunit protein (RIbeta). This application will investigate the hypothesis that deficient PKA-I isozyme activity is an integral signaling disorder that results in impaired CD4+,CD45RA/RO+- and CD8+,CD45RA/RO+-mediated helper and cytotoxic functions, respectively, which can be partially reconstituted by restoring physiologic PKA-I activity. Our specific aims are: (1) To investigate the role proteolysis/ubiquitination and translational silencing as mechanisms regulating RIbeta protein turnover in T cell lines and normal T cells and to investigate the role of abnormal proteolysis/ubiquitination and/or translational silencing in reduced/absent RIbeta protein expression in SLE T cells. (2) To determine whether deficient PKA-I activity affects all T cells or a specific T cell subset and its relationship to CD59 v expression. (3) To examine the role of the RIbeta2C2 holoenzyme in T cell effector functions in SLE and normal T cells. (4) To perform SLE multiplex family studies to determine (4a) The prevalence of RIbeta protein deficiency. (4a) Whether deficient PKA-I activity due to reduced/absent RIbeta protein is a heritable disorder in families of lupus probands. Thus, the significance of this research is its potential to explain how defective signaling circuitry within the T cell can lead to the aberrant T cell effector functions that result in lupus immunopathogenesis.

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种病因不明的自身免疫性疾病，其特征是T细胞效应功能受损。我们已经证明，由于缺乏I型蛋白激酶A（PKA-I）同工酶活性，蛋白激酶A催化的蛋白磷酸化受损。同工酶活性缺乏主要反映I型调节β亚基蛋白（RI β）显著减少或缺失。本申请将调查的假设，缺乏PKA-I同工酶活性是一个完整的信号转导障碍，导致受损的CD 4+，CD 45 RA/RO+-和CD 8+，CD 45 RA/RO+-介导的辅助细胞和细胞毒性功能，分别，这可以通过恢复生理PKA-I活性部分重建。我们的具体目标是：（1）研究蛋白水解/泛素化和翻译沉默作为调节T细胞系和正常T细胞中RI β蛋白周转的机制的作用，并研究异常蛋白水解/泛素化和/或翻译沉默在SLE T细胞中RI β蛋白表达减少/缺失中的作用。(2)确定PKA-I活性缺陷是否影响所有T细胞或特定T细胞亚群及其与CD 59 v表达的关系。(3)检测RI β 2C 2全酶在SLE和正常T细胞中T细胞效应子功能中的作用。(4)进行SLE多重家族研究以确定（4a）RI β蛋白缺乏症的患病率。(4a)在狼疮先证者家族中，由于RI β蛋白减少/缺失导致的PKA-I活性缺乏是否是一种遗传性疾病。因此，这项研究的意义在于它有可能解释T细胞内有缺陷的信号通路如何导致T细胞效应器功能异常，从而导致狼疮免疫发病机制。