Mechanistic and Therapeutic Investigations of Scleroderma

硬皮病的机制和治疗研究

• 批准号: 9304862
• 负责人: Harry C., III Dietz
• 金额: $ 35.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304862
• 关键词: Address; Adult; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocytes; Binding; Biological Assay; Blocking Antibodies; CD4 Positive T Lymphocytes; Calpain; Cell surface; Cells; Characteristics; Chemicals; Cicatrix; Collagen; Complex; Data; Dendritic Cells; Dendritic cell activation; Deposition; Dermal; Dermis; Developed Countries; Diffuse; Dimerization; Diphtheria Toxin; Disease; Disease Progression; Distal; Effector Cell; Etiology; Event; Extracellular Matrix Proteins; FBN1; Fibroblasts; Fibrosis; Gene Targeting; Genes; Genetic; Helper-Inducer T-Lymphocyte; Human; IL6 gene; Immune system; Immunologic Markers; Immunologics; Impairment; Infiltration; Inflammatory; Inherited; Integrin Binding; Integrins; Interferons; Interruption; Intervention; Intuition; Investigation; Knock-in Mouse; Lupus; MAPK3 gene; Maintenance; Malignant Neoplasms; Mediating; Mesenchymal; Mus; Mutation; Myofibroblast; Natural Immunity; Nucleic Acids; Onset of illness; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Performance; Pharmacology; Phenocopy; Phenotype; Plasma Cells; Predisposition; Prevention; Probability; Process; Production; Proteins; Psoriasis; Public Health; Pulmonary Fibrosis; Recruitment Activity; Recurrence; Role; Scleroderma; Severities; Signal Pathway; Skin; Surface; Syndrome; Systemic Scleroderma; T-Lymphocyte; TLR7 gene; Testing; Therapeutic; Tissues; Up-Regulation; Visceral; WNT Signaling Pathway; Work; adaptive immunity; antimicrobial peptide; autoinflammation; cathelicidin antimicrobial peptide; cell type; clinical development; cytokine; dimer; disorder prevention; genetic approach; improved; mouse model; neutralizing antibody; novel therapeutics; prevent; response; small molecule inhibitor; treatment response; treatment strategy

PROJECT SUMMARY The term scleroderma encompasses a diverse set of conditions that are unified by excessive collagen deposition in the skin and often internal organs. A common and severe but genetically intractable form called systemic sclerosis (SSc) shows adult-onset fibrosis in association with autoantibody production. Recently, we showed that a Mendelian form of scleroderma called stiff skin syndrome (SSS) is caused by mutations in the integrin-binding domain of fibrillin-1, a matrix protein that also regulates the activity of the profibrotic cytokine TGF. These mutations impair the ability of cells to make contact with fibrillin-1 via bridging interactions with integrins. Knock-in mouse models of SSS show fully-penetrant dermal fibrosis and all of the autoimmune abnormalities characteristic of SSc in association with tissue infiltration of activated plasmacytoid dendritic cells (pDCs) that are capable of orchestrating immunologic dysregulation and fibrosis through the production of inflammatory cytokines such as IFN- and IL6. Fibrosis and autoinflammation are prevented (or even reversed) in SSS mice with interventions that normalize the abnormally high expression of v3 integrin by pDCs; this complete rescue is phenocopied in SSS mice by blocking cellular signaling pathways known to influence pDC performance (e.g. TGF and ERK1/2). Notably, fibroblasts derived from patients with diffuse and active SSc also show concordant phenotypes and therapeutic responses. The work proposed in this application will fully exploit the first bona fide mouse model of a human presentation of scleroderma. Aim 1 will interrogate the relative contributions of perturbations in adaptive and innate immunity by building upon our exciting preliminary data showing full maintenance or complete abrogation of dermal fibrosis in SSS mice upon introduction of the complete null state for Rag2 (a factor required for the production of T and B cells) or conditional depletion of pDCs, respectively. We will also explore the relevance of a potential axis for matrix-initiated pDC activation that has been descriptively implicated in other autoimmune disorders and is now supported by our preliminary data for SSS. Aim 2 will assess the therapeutic potential of a pharmacologic antagonist of v3 integrin in scleroderma that is already in clinical development for cancer. It will also comprehensively scrutinize the role of specific pDC effector functions including the production of IFN-, IL6, or CXCL4 (a factor that shows excellent temporal correlation with the onset, severity and progression of SSc). Aim 3 will build upon prior work and our preliminary data showing that TGF-induced transition of diverse cell types to invasive collagen-producing myofibroblasts is critically dependent upon Wnt activity and the CAPN9/S2 dimeric calpain complex, respectively. These studies have the strong potential to unveil novel therapeutic strategies for SSS, SSc and perhaps more common presentations of fibrosis.

项目摘要 硬皮病一词包括一组不同的条件是统一的过度胶原蛋白 沉积在皮肤和内脏中。一种常见且严重但遗传上难以治愈的形式 称为系统性硬化症（SSc）的疾病显示与自身抗体产生相关的成人发病纤维化。 最近，我们发现了一种称为僵硬皮肤综合征（SSS）的孟德尔形式的硬皮病， 突变的整合素结合结构域中的整合素-1，一种基质蛋白，也调节的活性， 促纤维化细胞因子TGF β。这些突变削弱了细胞通过免疫球蛋白-1与细胞接触的能力。 桥接与整合素的相互作用。SSS的敲入小鼠模型显示完全渗透性真皮纤维化， 所有的自身免疫异常特征性的SSc与组织浸润的激活， 浆细胞样树突状细胞（pDC），能够协调免疫失调和纤维化 通过产生炎性细胞因子如IFN-γ和IL-6。纤维化和自身炎症是 通过使异常高表达正常化的干预措施， pDCs对pDCs整合素β 3的完全拯救;这种完全拯救通过阻断细胞信号传导在SSS小鼠中表现为表型 已知影响pDC性能的途径（例如TGF β 1和ERK 1/2）。值得注意的是，来源于 患有弥漫性和活动性SSc的患者也显示出一致的表型和治疗反应。的 在本申请中提出的工作将充分利用第一个真正的人类呈现的小鼠模型 硬皮病目标1将询问适应性和先天性干扰的相对贡献 豁免权的基础上，我们令人兴奋的初步数据显示，完全维持或完全废除 在引入Rag 2的完全无效状态后，SSS小鼠中的真皮纤维化（Rag 2的表达所需的因子） T和B细胞的产生）或pDC的条件性消耗。我们亦会探讨 基质启动的pDC激活的潜在轴的相关性，其已经被间接地牵连到 其他自身免疫性疾病，现在支持我们的初步数据SSS。目标2将评估 已经在临床中的硬皮病中的整合素的药理学拮抗剂的治疗潜力 癌症的发展。它还将全面审查特定pDC效应子功能的作用， 包括IFN-γ、IL-6或CXCL-4的产生（一种与肿瘤细胞增殖表现出极好的时间相关性的因素）。 SSc的发病、严重程度和进展）。目标3将建立在以前的工作和我们的初步数据显示， TGF β诱导的不同类型细胞向侵袭性胶原蛋白生成肌成纤维细胞的转变是至关重要的， 分别依赖于Wnt活性和CAPN 9/S2二聚体钙蛋白酶复合物。这些研究 揭示SSS，SSc以及可能更常见的新治疗策略的强大潜力 纤维化的表现。