Complement in inflammatory diseases: mechanisms & therapeutic modulation

描述（由申请人提供）：虽然炎症是许多临床疾病的共同组成部分，但促成因素可以是不同的。近年来，补体系统与越来越多的炎症相关，包括急性和慢性组织炎症、生物材料不良反应和移植排斥反应。很明显，宿主细胞上过度或不充分控制的补体激活可导致免疫失衡，氧化应激或感染等因素加剧了免疫失衡，可能会引发补体、炎症和组织损伤之间的恶性循环。因此，补体的治疗性调节成为炎症过程上游抑制的有吸引力的靶点，但需要深刻理解潜在的过程，确定有益的靶点，并仔细选择合适的抑制剂。因此，该项目采用高度整合和整体的方法来描述补体参与炎症的共同和独特特征，并为改进治疗策略开辟途径。为此目的，三种疾病模型是广泛的补体介导条件的代表，对医疗保健和诊所有很大的影响，将进行彻底的调查。尽管血液透析和肾移植的炎症反应（项目2）代表了人工和外来表面补体激活的独特紊乱和终末期肾脏疾病的主要并发症，但牙周炎（项目3）是一种新兴的、非常有吸引力的局部组织炎症模型，具有很强的传染性成分。利用相关的体外实验、灵敏的仪器方法（Core 6）和啮齿动物和非人灵长类动物的转化模型，研究疾病过程与补体触发和活性的关系，以及与相关途径（如TLR）、对下游炎症过程的影响以及调节因素（如氧化损伤、感染）的影响。将产生多种有效的、经过验证的、途径特异性和/或靶向补体抑制剂（项目1，核心B），允许对每种疾病中涉及的补体途径和过程进行解剖。这个“抑制剂工具箱”包括中枢C3抑制剂compstatin的类似物，它将作为基准化合物，以及在单个起始、扩增和效应途径上起作用的实体。疗效、药代动力学、给药和靶向特性的优化将以项目2和项目3疾病模型的结果和要求为指导。与此同时，在这些相关疾病模型中评估有希望的和预先验证的抑制剂候选物有望快速转化为治疗概念。这种P01的已建立的模型、方法和抑制剂可以很容易地应用于未来的疾病研究。因此，该P01将对补体相关疾病的阐明和管理产生重大影响，并使患者和研究界受益。

DESCRIPTION (provided by applicant): While inflammation is a common component of many clinical disorders, the contributing factors can be distinct. In recent years, the complement system has been associated with a growing number of inflammatory conditions that include acute and chronic tissue inflammation, adverse reactions to biomaterials, and transplant rejection. It is evident that excessive or insufficiently controlled complement activation on host cells can cause an immune imbalance that, exacerbated by factors such as oxidative stress or infection, may fuel a vicious cycle between complement, inflammation, and tissue damage. As a consequence, therapeutic modulation of complement emerges as attractive target for upstream inhibition of inflammatory processes but requires profound understanding of underlying processes, identification of rewarding targets, and careful selection of suitable inhibitors. This Program Project therefore employs a highly integrated and holistic approach to describe common and distinct denominators of complement involvement in inflammatory conditions and open avenues for improved therapeutic strategies. For this purpose, three disease models that are representative of the wide spectrum of complement-mediated conditions and have high impact for health care and the clinic will be thoroughly investigated. Whereas inflammatory reactions to hemodialysis and kidney transplantation (Project 2) represent distinct disorders of complement activation by artificial and foreign surfaces and major complications in end-stage renal disease, periodontitis (Project 3) is an emerging and very attractive model of local tissue inflammation with a strong infectious component. Using relevant in vitro assays, sensitive instrumental methods (Core 6), and translational models in rodents and non-human primates, disease processes will be investigated in relation to complement triggers and activity, but also to associated pathways (e.g., TLR), effects on downstream inflammatory processes, and influences of modulating factors (e.g., oxidative damage, infection). A diverse panel of potent, validated, pathway-specific and/or targeted complement inhibitors will be generated (Project 1, Core B) that allows for the dissection of involved complement pathways and processes in each disease. This 'inhibitor toolbox' includes analogs of the central C3 inhibitor compstatin, which will serve as a benchmark compound, and entities acting at individual initiation, amplification, and effector pathways. Optimization of efficacy, pharmacokinetic, administration, and targeting properties will be guided by results and requirements of the disease models of Projects 2 & 3. At the same time, the evaluation of promising and pre-validated inhibitor candidates in such relevant disease models is expected to allow rapid translation into therapeutic concepts. Established models, methods, and inhibitors of this P01 can easily be applied to future disease studies. Thus, this P01 will have a high impact on the elucidation and management of complement-related disease and benefit patients and the research community.