Role of Apoptosis in Pemphigus

细胞凋亡在天疱疮中的作用

• 批准号: 7029521
• 负责人: NING LI
• 金额: $ 5.23万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029521
• 关键词: apoptosis; autoantibody; cadherins; disease /disorder etiology; disease /disorder model; human tissue; immunocytochemistry; immunoglobulin G; inhibitor /antagonist; keratinocyte; laboratory mouse; pathologic process; pemphigus; western blottings

DESCRIPTION (provided by applicant): Pemphigus is a group of life-threatening autoimmune blistering diseases characterized by pathogenic IgG autoantibodies against desmogleins (Dsg) and intraepidermal cell-cell detachment (acantholysis). .Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are two classical forms of pemphigus. While PF is mediated by autoantibodies to Dsg1, PV is caused by autoantibodies against Dsg3. The pathogenesis of pemphigus is not fully understood. In preliminary studies, we have shown that pathogenic antibodies from PF and PV patients were able to induce epidermal cell apoptosis when passively transferred into neonatal mice. Remarkably, time-course study indicated that the onset of apoptosis preceded and accompanied the onset of acantholysis. In this R03 pilot project, we will further characterize the induction of apoptosis in the mouse models of PF and PV and test the hypothesis that apoptosis contributes to the pathogenesis of pemphigus. In Aim 1, we will confirm the induction of keratinocyte apoptosis in the mouse models of pemphigus by three independent methods. We will also verify that the induction of apoptosis is through the action of anti-Dsgl and anti-Dsg3 autoantibodies. In Aim 2, we will define the key apoptotic mediators activated by pemphigusIgG. Time course experiments will be performed to reveal the sequential activation of apoptotic modulators by means of immunohistochemistry, immunoblotting, and enzymatic assays. In Aim 3, we will test whether blocking apoptosis could inhibit or attenuate pemphigus lesions. We will attempt to prevent induced apoptosis by using apoptosis inhibitors and mice with known apoptotic defects. The data derived from this study is expected to provide new insight into the role of desmogleins in keratinocyte survival/apoptosis and advance our understanding of the pathogenesis of pemphigus. This study may open a novel avenue for therapeutic intervention. The work is likely to lead to a more comprehensive R01 project investigating the apoptotic pathways involved in pemphigus and its pathogenic role in pemphigus.

描述(申请人提供)：天疱疮是一组危及生命的自身免疫性水疱性疾病，其特征是致病的抗桥粒细胞球蛋白自身抗体(DSG)和表皮内细胞-细胞分离(棘层松解症)。叶状天疱疮(Pf)和寻常型天疱疮(PV)是两种经典的天疱疮类型。PF是由抗DSG1的自身抗体介导的，而PV是由抗Dsg3的自身抗体引起的。天疱疮的发病机制尚不完全清楚。在初步研究中，我们已经证明了来自PF和PV患者的致病抗体在被动转移到新生小鼠体内时能够诱导表皮细胞凋亡。 值得注意的是，时程研究表明，细胞凋亡的发生先于并伴随着细胞的发生。 棘层松解术。在这个R03试点项目中，我们将进一步表征小鼠对细胞凋亡的诱导 建立PF和PV模型，验证细胞凋亡参与天疱疮发病机制的假说。 在目标1中，我们将证实三种化合物对天疱疮小鼠模型角质形成细胞的诱导凋亡作用。 独立的方法。我们还将验证，诱导细胞凋亡是通过抗DSGL和抗Dsg3自身抗体的作用。在目标2中，我们将定义天疱疮免疫球蛋白激活的关键的细胞凋亡介质。时间进程实验将通过免疫组织化学、免疫印迹和酶分析来揭示凋亡调节剂的顺序激活。在目标3中，我们将测试阻断细胞凋亡是否可以抑制或减轻天疱疮病变。我们将尝试通过使用凋亡抑制剂和存在已知凋亡缺陷的小鼠来防止诱导细胞凋亡。这项研究的数据有望为桥粒蛋白在角质形成细胞存活/凋亡中的作用提供新的见解，并促进我们对天疱疮发病机制的理解。这项研究可能为治疗干预开辟一条新的途径。这项工作可能会导致一个更全面的R01项目，调查天疱疮中涉及的凋亡途径及其在天疱疮中的致病作用。