KFO 303: Pemphigoid Diseases - Molecular Pathways and their Therapeutic Potential

KFO 303：类天疱疮疾病 - 分子途径及其治疗潜力

• 批准号: 269234613
• 金额: --
• 依托单位: Institut für Experimentelle Medizin (IEM)
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/269234613?language=en
• 关键词: KFO; 303; Pemphigoid; Diseases; Molecular

Pemphigoid diseases (PD) are a group of severe, closely related, chronic, autoantibody (AAb)-induced, subepidermal blistering skin diseases caused by an immune response directed to defined autoantigens serving as adhesion molecules within in the hemidesmosomal anchoring complex at the dermal-epithelial junction (DEJ) of squamous epithelia, including the skin. In the effector phase of this immune response, inflammatory cells are recruited into the dermis and release mediators, including proteases, compromising dermal-epidermal adhesion. Consequently, skin blisters and erosions develop.PDs mainly affect elderly and are associated with a high mortality. With their incidence rising, they constitute a growing health concern. Treatment options are limited and often elicit severe adverse effects. Development of novel therapeutic strategies takes sound understanding of PD pathogenesis. The molecular mechanisms driving PDs, however, are only incompletely understood. The mere presence of AAbs alone, although a prerequisite for skin inflammation, is not sufficient to initiate the effector phase. A pivotal question therefore is how immune effector cell recruitment into the dermis is initiated, amplified, and finally perpetuated. Effectively and specifically blunting effector cell recruitment in a therapeutic effort is presumably key to control PD. The Department of Dermatology at the University of Lübeck is one of few academic centers worldwide specialized in both research and treatment of PDs. We have developed unique mouse models of PDs and have established a significant PD patient cohort. This has allowed us to shed some light on the pathogenesis of PDs, which has turned out to be more complex than previously anticipated. Recently, we have made new exciting discoveries, specifically on the effector phase of PDs, now kindling this Clinical Research Unit (CRU) proposal. Our goal is to uncover the factors triggering and driving skin inflammation and to provide a comprehensive model for the effector phase of PDs. We will particularly elucidate the mechanisms initiating, amplifying, and perpetuating effector cell recruitment, and we will translate these new insights into novel therapeutics, preventive strategies, and biomarkers. In this context, PDs will serve as paradigm for the elucidation of the effector phase of AAb-driven autoimmune diseases in general. Unlike in PDs, the autoantigens in the majority of autoimmune diseases are unknown, thus complicating the elucidation of the effector phase of most autoimmune diseases, especially its early stage when tissue inflammation is just emerging.By this CRU, we will establish a permanent translational research unit at the University of Lübeck and will train particularly physician scientists. The CRU will further strengthen the major research focus ¿Infection and Inflammation¿ of the University of Lübeck.

类天疱疮疾病 (PD) 是一组严重的、密切相关的、慢性的自身抗体 (AAb) 诱导的表皮下起泡皮肤病，由针对特定自身抗原的免疫反应引起，所述自身抗原作为鳞状上皮（包括皮肤）真皮上皮交界处 (DEJ) 半桥粒锚定复合物中的粘附分子。在这种免疫反应的效应器阶段，炎症细胞被招募到真皮中并释放介质，包括蛋白酶，损害真皮-表皮粘附。因此，皮肤会出现水疱和糜烂。帕金森病主要影响老年人，死亡率很高。随着其发病率的上升，它们构成了日益严重的健康问题。治疗选择有限，并且常常引起严重的副作用。开发新的治疗策略需要对 PD 发病机制有充分的了解。然而，驱动 PD 的分子机制尚不完全清楚。 AAb 的单独存在虽然是皮肤炎症的先决条件，但不足以启动效应阶段。因此，一个关键问题是免疫效应细胞招募到真皮中是如何启动、放大并最终持续存在的。在治疗过程中有效且特异性地减弱效应细胞的募集可能是控制 PD 的关键。吕贝克大学皮肤科是全球为数不多的专门从事帕金森病研究和治疗的学术中心之一。我们开发了独特的 PD 小鼠模型，并建立了重要的 PD 患者队列。这让我们对帕金森病的发病机制有了一些了解，事实证明帕金森病的发病机制比之前预期的更为复杂。最近，我们取得了令人兴奋的新发现，特别是在 PD 的效应器阶段，现在引发了这项临床研究单位 (CRU) 的提案。我们的目标是揭示触发和驱动皮肤炎症的因素，并为 PD 的效应阶段提供全面的模型。我们将特别阐明启动、放大和维持效应细胞募集的机制，并将这些新见解转化为新的治疗方法、预防策略和生物标志物。在这种情况下，PD 将作为阐明 AAb 驱动的自身免疫性疾病效应阶段的范例。与PD不同，大多数自身免疫性疾病中的自身抗原是未知的，因此使大多数自身免疫性疾病的效应阶段的阐明变得复杂，特别是组织炎症刚刚出现的早期阶段。通过这个CRU，我们将在吕贝克大学建立一个永久性的转化研究单位，并将专门培训医师科学家。 CRU将进一步加强吕贝克大学的主要研究重点“感染与炎症”。