Role of Apoptosis in Pemphigus

细胞凋亡在天疱疮中的作用

• 批准号: 7394980
• 负责人: NING LI
• 金额: $ 4.94万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394980
• 关键词: Acantholysis; Adrenal Cortex Hormones; Animals; Antibodies; Apoptosis; Apoptosis Inhibitor; Apoptotic; Area; Attenuated; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Binding; Biochemistry; Biological Assay; Bulla; Cells; Data; Defect; Dermatology; Disease; Epidermis; Grant; Immunoblotting; Immunoglobulin G; Immunohistochemistry; Immunology; Immunosuppressive Agents; In Vitro; Induction of Apoptosis; Injection of therapeutic agent; Institution; Knowledge; Lead; Lesion; Life; Mediating; Mediator of activation protein; Methods; Modality; Molecular; Molecular Biology; Morbidity - disease rate; Morphology; Mus; Neonatal; Nuclear; Pathogenesis; Pathway interactions; Patients; Pemphigus; Pemphigus Vulgaris; Pilot Projects; Play; Positioning Attribute; Protocols documentation; Purpose; Research; Research Design; Research Personnel; Resources; Role; Skin; Study Section; Testing; Therapeutic Intervention; Time; United States National Institutes of Health; Work; base; caspase-3; concept; design; desmoglein; expectation; human BIRC3 protein; human disease; in vivo; insight; keratinocyte; mortality; mouse model; multidisciplinary; novel; novel therapeutics; prevent; protective effect; research study; response; skin disorder

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 pemphigus IgG. 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.

天疱疮是一组以致病性 IgG 为特征的危及生命的自身免疫性水疱性疾病 抗桥粒芯糖蛋白 (Dsg) 和表皮内细胞-细胞脱离（棘层松解）的自身抗体。 。 落叶型天疱疮 (PF) 和寻常型天疱疮 (PV) 是天疱疮的两种经典形式。虽然 PF 是 PV由针对Dsg1的自身抗体介导，PV由针对Dsg3的自身抗体引起。发病机制 天疱疮尚未完全了解。在初步研究中，我们已经表明 PF 的致病性抗体 当PV患者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凋亡的发生。 棘层松解症。在这个 R03 试点项目中，我们将进一步表征小鼠细胞凋亡的诱导 PF 和 PV 模型并检验细胞凋亡有助于天疱疮发病机制的假设。 在目标 1 中，我们将通过三种方法确认天疱疮小鼠模型中角质形成细胞凋亡的诱导 独立的方法。我们还将验证细胞凋亡的诱导是通过抗 Dsgl 的作用 和抗 Dsg3 自身抗体。在目标 2 中，我们将定义天疱疮激活的关键细胞凋亡介质 免疫球蛋白G。将进行时程实验以揭示细胞凋亡调节剂的顺序激活 通过免疫组织化学、免疫印迹和酶测定的方法。在目标 3 中，我们将测试是否 阻断细胞凋亡可以抑制或减轻天疱疮病变。我们将尽力防止诱发 通过使用细胞凋亡抑制剂和具有已知细胞凋亡缺陷的小鼠来进行细胞凋亡。由此得出的数据 该研究有望为桥粒芯糖蛋白在角质形成细胞存活/凋亡中的作用提供新的见解 增进我们对天疱疮发病机制的了解。这项研究可能会开辟一条新途径 治疗干预。这项工作可能会导致一个更全面的 R01 项目调查 天疱疮涉及的细胞凋亡途径及其在天疱疮中的致病作用。