Cell Cycle Inhibition in Systemic Autoimmunity

系统性自身免疫中的细胞周期抑制

• 批准号: 7016286
• 负责人: DWIGHT H KONO
• 金额: $ 45.38万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7016286
• 关键词: CD95 molecule; T cell receptor; antigen antibody reaction; apoptosis; autoantigens; autoimmunity; biological signal transduction; cell cycle; cell differentiation; cell senescence; cyclin dependent kinase; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; helper T lymphocyte; immune response; immunocytochemistry; immunologic memory; kinase inhibitor; laboratory mouse; leukocyte activation /transformation; lymphocytic choriomeningitis virus; oncoprotein p21; pathologic process; protein structure function; systemic lupus erythematosus

DESCRIPTION (provided by applicant): This project will focus on defining the role of the cell cycle inhibitor, p21, in normal immune and autoimmune responses. The cell cycle plays a critical role in determining the fate and differentiation state of cells. It is therefore highly regulated by complexes of proteins such as cyclin, cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs)7 which in turn are regulated by external stimuli through a number of intracellular signaling pathways. We found that high levels of certain CDKIs, including p21, p18 and p27 are present in activated/memory (CD44hl) phenotype CD4+ T cells in lupus-prone male BXSB mice. Such T cells are commonly increased in lupus and we postulated that repeated stimulation of self-antigen-reactive T cells might lead to a state similar to "replicative senescence", where T cells are no longer cycling, but are resistant to apoptosis, accumulate and transcribe autoimmune-promoting pro-inflammatory cytokines. To test this possibility, we generated and examined lupus-prone mice deficient in p21 and have performed preliminary studies of p27 knockout autoimmune mice. Male BXSB mice lacking p21 exhibited marked reduction in disease associated with enhanced apoptosis of T and B lymphocytes and significantly decreased accumulation of activated/memory CD4+ T cells. Initial studies of p27- deficient male BXSB mice also revealed reduced mortality. To further examine the role of CDKIs in autoimmunity and normal immune response four aims are proposed. The first will determine the effect of p21 deficiency on another genetically distinct lupus-prone strain, NZB.NZW-Lbw5, an interval-specific congenic line derived from NZB and NZW mice. The second aim will determine whether expression of p21 in T cells is critical for the development of autoimmunity. The third aim will examine the effect of p21 deficiency on immune responses to a foreign antigen and LCMV infection. The final aim will determine the role of Fas-induced apoptosis in the disease reduction observed in BXSB-p21"7" mice. These studies should yield important new insights into the significance and role of p21 in systemic autoimmunity and in host response to foreign antigens.

描述（由申请人提供）： 该项目将重点定义细胞周期抑制剂 p21 在正常免疫和自身免疫反应中的作用。细胞周期在决定细胞的命运和分化状态方面起着至关重要的作用。因此，它受到细胞周期蛋白、细胞周期蛋白依赖性激酶 (CDK) 和 CDK 抑制剂 (CDKI)7 等蛋白质复合物的高度调节，而这些蛋白质复合物又通过许多细胞内信号通路受到外部刺激的调节。我们发现，在易患狼疮的雄性 BXSB 小鼠中，激活/记忆 (CD44hl) 表型 CD4+ T 细胞中存在高水平的某些 CDKI，包括 p21、p18 和 p27。这种 T 细胞在狼疮中通常会增加，我们推测反复刺激自身抗原反应性 T 细胞可能会导致类似于“复制性衰老”的状态，其中 T 细胞不再循环，但能够抵抗凋亡、积累和增殖。转录促进自身免疫的促炎细胞因子。为了测试这种可能性，我们生成并检查了 p21 缺陷的易患狼疮的小鼠，并对 p27 敲除的自身免疫小鼠进行了初步研究。缺乏 p21 的雄性 BXSB 小鼠表现出与 T 和 B 淋巴细胞凋亡增强相关的疾病显着减少，并且活化/记忆 CD4+ T 细胞的积累显着减少。对 p27 缺陷的雄性 BXSB 小鼠的初步研究也显示死亡率降低。为了进一步研究 CDKI 在自身免疫和正常免疫反应中的作用，提出了四个目标。第一个将确定 p21 缺陷对另一种遗传上不同的狼疮倾向品系 NZB.NZW-Lbw5 的影响，NZB.NZW-Lbw5 是一种源自 NZB 和 NZW 小鼠的区间特异性同系系。第二个目标将确定 T 细胞中 p21 的表达是否对于自身免疫的发展至关重要。第三个目标是检查 p21 缺陷对外来抗原和 LCMV 感染的免疫反应的影响。最终目标将确定 Fas 诱导的细胞凋亡在 BXSB-p21"7" 小鼠中观察到的疾病减少中的作用。这些研究应该对 p21 在系统性自身免疫和宿主对外来抗原反应中的重要性和作用产生重要的新见解。