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Inflammasomes and Gasdermins in the Pathogenesis of Bullous Pemphigoid

大疱性类天疱疮发病机制中的炎症小体和 Gasdermin

基本信息

批准号：
10090561
负责人：
Stephen Kovacs
金额：
$ 5.1万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-24 至 2022-01-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090561
关键词：
Adrenal Cortex Hormones Affect Antibodies Apoptotic Atopic Dermatitis Autoantibodies Autoimmune Diseases Automobile Driving Basement membrane Basic Science Binding Bone Marrow Transplantation Bulla Bullous Pemphigoid CASP1 gene CASP3 gene Cell Death Cell membrane Cells Characteristics Clinical Skills Complement Complement Membrane Attack Complex Cytolysis Data Dermis Development Diagnosis Disease Elderly Epidermis Europe Face Family Foundations Future Genes Goals Grant Hemidesmosomes Immune Immunology In Vitro Infection Inflammasome Inflammation Inflammation Mediators Inflammatory Knock-out Knockout Mice Knowledge Learning Liquid substance Lytic Maps Mediating Mediator of activation protein Membrane Modeling Mus Natural Immunity Neutrophil Infiltration Participant Passive Transfer of Immunity Pathogenesis Pathogenicity Pathology Pathway interactions Patients Peptide Hydrolases Physicians Protein Family Proteins Psoriasis Radiation Tolerance Recurrence Relapse Research Resistance Role Scientist Skin System Therapeutic Training United States career caspase 14 cell type cytokine effective therapy improved in vivo in vivo Model insight keratinocyte medical schools member mouse model neutrophil new therapeutic target novel novel therapeutics prevent protein activation protein complex radioresistant reconstitution recruit skin disorder skin organogenesis therapeutic development

项目摘要

SUMMARY/ABSTRACT Bullous pemphigoid is an autoimmune disorder characterized by the emergence of large, fluid-filled blisters on the skin of affected patients. It is caused by pathogenic antibodies that target BP180, a component of the hemidesmosomes that attach basal keratinocytes to the basement membrane of the epidermis. The antibodies promote inflammation and neutrophil recruitment, leading to the destruction of hemidesmosomes and separation of the epidermis from the dermis. Bullous pemphigoid is the most common blistering autoimmune disorder of the skin, and 10.8% of patients in the United States die within one year of diagnosis. Even in patients successfully treated for bullous pemphigoid, recurrence is common. Thus, novel therapeutics to better treat and prevent recurrence of bullous pemphigoid are needed. Our preliminary data shows that the NLRP3 inflammasome pathway and its end product, the inflammatory cytokine IL-1b, are required for neutrophil recruitment and blister formation in a well-established mouse model of bullous pemphigoid. Similarly, we observed that mice deficient in the keratinocyte-specific protein gasdermin A had significantly lower levels of IL-1b within the skin and were resistant to blister formation. Gasdermin A is a member of a family of proteins that includes gasdermin D, which was recently shown to mediate IL-1b release and lytic cell death downstream of inflammasome activation in immune cells. Therefore, we hypothesize that gasdermin A similarly acts downstream of inflammasome activation within keratinocytes to promote inflammation of the skin and bullous pemphigoid pathology. In AIM 1, we will determine in which cell types the NLRP3 inflammasome is activated in the mouse model of bullous pemphigoid using bone marrow transplants and cell type-specific IL-1b knockouts, and we will assess the role of terminal components of complement in activating NLRP3 using mice deficient in membrane attack pore formation. In AIM 2, we will compare the role and activation mechanism of gasdermin A and gasdermin D in the mouse model of bullous pemphigoid using mice deficient in gasdermin A and gasdermin D in the in vivo model of bullous pemphigoid, and by reconstituting gasdermin activation pathways in vitro. This grant is significant because it will provide foundational knowledge that may aid in the development of novel therapeutics that target inflammasomes and gasdermins to treat bullous pemphigoid. Furthermore, this grant will more broadly provide insights into the functions of keratinocytes as active participants of innate immunity and gasdermins as mediators of inflammation in the skin. Notably, to our knowledge, this would be the first in-depth characterization of gasdermin A as a mediator of skin inflammation. Thus, insights gained from this grant may improve our understanding of the pathogenesis of bullous pemphigoid and other inflammatory conditions of the skin as well as our understanding of how the skin protects against infection.

摘要/摘要： -- 大疱性类天疱疮是一种自身免疫性疾病，其特点是大量大量液体充盈。水泡发生在受影响的患者的皮肤上。它可能是由针对BP180的致病病毒抗体引起的，而BP180是一种重要的成分。在连接基底角质形成细胞的半嵌合体中，有两个半嵌合体连接到表皮的基底和膜层。抗体可以促进炎症反应和中性粒细胞募集，从而导致半桥粒细胞的进一步破坏。表皮和真皮的分离。大疱性类天疱疮是最常见的疱疹。自身免疫性疾病是一种常见的皮肤疾病，在美国，10.8%的患者会在确诊后一年内死亡。即使在那些成功治疗了大疱性类天疱疮的患者中，复发也是很常见的。因此，一种新的治疗方法。为了更好地治疗和预防大疱性类天疱疮的复发，迫切需要。我们的初步数据显示，NLRP3是炎症性小体的主要途径，也是其最终产品。炎性细胞因子IL-1b是中性粒细胞募集和水泡形成所必需的。小鼠是大疱性类天疱疮的模型动物。同样，我们也观察到小鼠缺乏对角质形成细胞的特异性反应。蛋白质制造商Gasdermin的A组显著降低了皮肤组织中IL-1b的水平，而且它们对水泡的抵抗力较强。形成。Gasdermin是一个重要蛋白质家族的成员之一，其中包括最近被发现的Gasdermin D.D。显示了它可以调节IL-1b的释放和溶血细胞的死亡，以及免疫细胞中炎性小体激活的下游过程。因此，我们可以假设，Gasdermin-A在体内同样作用于炎症小体激活的下游过程。角质形成细胞有助于促进皮肤的炎症反应和大疱性类天疱疮的病理改变。在AIM实验1中，我们将无法确定在小鼠体内，NLRP3和炎症体基因的哪种细胞类型被激活。大疱性类天疱疮患者使用骨髓移植的模型，以及针对细胞类型的IL-1b基因敲除的模型，我们将继续下去。利用细胞膜上存在缺陷的小鼠，评估补体蛋白的末端成分在激活NLRP3中的重要作用。攻击形成毛孔。在AIM第二章中，我们将不会比较Gasdermin A股和A股的主要作用和激活机制。 Gasdermin D参与了大疱性类天疱疮小鼠模型的建立，使用了Gasdermin A和Gasdermin D缺乏基因的小鼠。在体内建立了大疱性类天疱疮的模型，并在体外通过重组Gasdermin蛋白的激活途径进行了研究。这笔赠款非常重要，因为它不会提供基础知识，可能会帮助我们实现可持续发展。许多新的治疗方法可以针对炎症性小体，也可以用来治疗大疱性类天疱疮。这项研究将更广泛地提供对角质形成细胞的重要功能的深入了解，因为这些细胞是天然角质形成细胞的积极参与者。免疫力和皮肤炎是皮肤炎症的主要调节因子。值得注意的是，根据我们目前的知识，这种情况不会发生。这是加斯德明作为皮肤炎症的主要调解人的第一个深入的定性研究。因此，他们获得了更多的见解。从这个角度来看，赠款可能会提高我们对大疱性类天疱疮和其他疾病的发病机制的更多了解。炎症性疾病是皮肤的问题，也是我们对皮肤如何保护身体免受感染的进一步理解。