Molecular Pathogenesis of Immune Dysfunction In Wiskott-Aldrich-Syndrome

Wiskott-Aldrich 综合征免疫功能障碍的分子发病机制

• 批准号: 8077332
• 负责人: YATIN M VYAS
• 金额: $ 37.12万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077332
• 关键词: Accounting; Actins; Address; Atopic Dermatitis; Autoimmune Diseases; Autoimmunity; Automobile Driving; Bacterial Infections; Binding; Biological; Boxing; CD4 Positive T Lymphocytes; Cell Communication; Cell Line; Cell Nucleus; Cell Shape; Cell physiology; Cells; Childhood; Clinical; Colitis; Commit; Contusions; Cytochalasin D; Cytoskeleton; Defect; Dendritic Cells; Development; Disease; ES01; Eczema; Equilibrium; Event; Exhibits; F-Actin; Fostering; Foundations; Functional disorder; Future; Gene Proteins; Generations; Genes; Genetic Transcription; Genotype; Grant; Health; Helper-Inducer T-Lymphocyte; Hemorrhage; Heterogeneity; Human; Hyperactive behavior; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Deficiency Syndromes; Individual; Infection; Interferons; Interleukin-13; Interleukin-17; Interleukin-6; Lavandula; Life; Ligands; Link; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Modeling; Molecular; Mutation; Nature; Notch Signaling Pathway; Nuclear; Nuclear Translocation; Opportunistic Infections; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral; Phase; Phenotype; Phosphorylation; Population; Production; Protein Deficiency; Proteins; RNA Interference; Recurrence; Regulation; Repression; Review Literature; Role; STAT1 gene; STAT4 gene; Severities; Severity of illness; Shapes; Signal Pathway; Signal Transduction; Specificity; Synapses; T-Lymphocyte; T-bet protein; Tertiary Protein Structure; Testing; Th1/Th2 Differentiation Pathway; Thrombocytopenia; Virus Diseases; Wiskott-Aldrich Syndrome; Work; base; clinical phenotype; cytokine; design; functional outcomes; immunological synapse; inhibitor/antagonist; insight; interleukin-12 receptor; jasplakinolide; knock-down; latrunculin A; molecular phenotype; mutant; new therapeutic target; notch protein; novel; polymerization; programs; reconstitution; response; segregation; transcription factor

DESCRIPTION (provided by applicant): Wiskott-Aldrich syndrome (WAS) is an X-linked immune deficiency arising from mutations in the WAS protein (WASp) gene, required for the proper functioning of T helper cell (Th), important for shaping the adaptive immune response. The clinical severity of disease can range from mild to severe, even in patients with the identical WASp mutation. The biological basis for this range of adaptive immune dysfunction is not known. The Th:DC interaction initiates multiple signaling pathways specific for Th1 differentiation. The classical Th1 signaling pathway requires the formation of a mature Th1-signalosome (IFN3R+TCR2) at the Th immune synapse (ThIS) and downstream activation of STAT1 and T-bet, leading to transcription of IFN-3. In parallel, ITK-dependent phosphorylation of T-bet is required for deactivation of GATA-3, the Th2 transcription factor. Finally, the Notch signaling pathway has effects on both Th1 and Th2 differentiation. How are these seemingly disparate signaling pathways organized into a functional Th1 developmental paradigm? In this proposal we will test the hypothesis that WASp is critical for both TCR-dependent and Notch-dependent pathways of Th1 activation, and propose that the adaptor function of WASp organizes Th1 developmental responses by fostering interactions between Notch, ITK and T-bet. We posit that the severity of WAS clinical phenotype mirrors the degree of Th dysfunction imparted by WASp mutations that disrupt these interactions. In Aim 1, we will test the hypothesis that WASp is critical for the proper functioning of the TCR-dependent pathway of Th1 differentiation. Aim 2 will test the hypothesis that WASp is critical for Notch-signaling in Th1 differentiation. Finally, Aim 3 will test the hypothesis that the severity of WAS clinical phenotype is mirrored in the degree of Th dysfunction. These studies should provide new insights into the function of WASp in the development of the adaptive immune response in health and disease, which may be of value in developing new therapeutic targets. Lay-term summary: Wiskott-Aldrich syndrome (WAS) is a genetically transmitted systemic immune deficiency resulting from a defect in a protein called WASP and manifesting clinically in severe recurrent infections, easy bruising and bleeding, autoimmunity, and cancers. The studies in this proposal will examine the function of WASP at the molecular level to determine the causes of the above clinical complications of WAS. These studies should lay the foundation for designing novel therapies in the future, for this life-threatening, debilitating disease of the childhood.

描述（由申请人提供）：Wiskott-Aldrich 综合征 (WAS) 是一种由 WAS 蛋白 (WASp) 基因突变引起的 X 连锁免疫缺陷，WAS 蛋白 (WASp) 基因是 T 辅助细胞 (Th) 正常发挥功能所必需的，对于形成适应性免疫反应非常重要。疾病的临床严重程度可以从轻度到重度不等，即使是具有相同 WASp 突变的患者也是如此。这种适应性免疫功能障碍的生物学基础尚不清楚。 Th:DC 相互作用启动多个针对 Th1 分化的信号通路。经典的 Th1 信号通路需要在 Th 免疫突触 (ThIS) 处形成成熟的 Th1 信号体 (IFN3R+TCR2)，并激活下游 STAT1 和 T-bet，从而导致 IFN-3 的转录。同时，T-bet 的 ITK 依赖性磷酸化是 Th2 转录因子 GATA-3 失活所必需的。最后，Notch 信号通路对 Th1 和 Th2 分化都有影响。这些看似不同的信号通路如何组织成功能性 Th1 发育模式？在本提案中，我们将测试 WASp 对于 TCR 依赖性和 Notch 依赖性 Th1 激活途径至关重要的假设，并提出 WASp 的适配器功能通过促进 Notch、ITK 和 T-bet 之间的相互作用来组织 Th1 发育反应。我们假设 WAS 临床表型的严重程度反映了 WASp 突变破坏这些相互作用所造成的 Th 功能障碍的程度。在目标 1 中，我们将检验以下假设：WASp 对于 TCR 依赖性 Th1 分化途径的正常运作至关重要。目标 2 将检验 WASp 对于 Th1 分化中的 Notch 信号传导至关重要的假设。最后，目标 3 将检验以下假设：WAS 临床表型的严重程度反映在 Th 功能障碍的程度中。这些研究应该为WASp在健康和疾病中适应性免疫反应发展中的功能提供新的见解，这可能对开发新的治疗靶点具有价值。简单概括：Wiskott-Aldrich 综合征 (WAS) 是一种遗传性系统性免疫缺陷，由一种名为 WASP 的蛋白质缺陷引起，临床表现为严重的反复感染、容易瘀伤和出血、自身免疫和癌症。本提案中的研究将从分子水平检验WASP的功能，以确定WAS上述临床并发症的原因。这些研究应该为未来针对这种危及生命、使人衰弱的儿童疾病设计新疗法奠定基础。