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常见组成部分，但影响因素可能不同。近年来，补体系统与越来越多的炎症性疾病相关，包括急性和慢性组织炎症、对生物材料的不良反应和移植排斥。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，其由诸如氧化应激或感染的因素加剧，可加剧补体、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，但需要对潜在过程的深刻理解，识别奖励靶点，并仔细选择合适的抑制剂。因此，该计划项目采用高度综合和整体的方法来描述炎症条件下补体参与的常见和不同的激活剂，并为改善治疗策略开辟途径。为此，将彻底研究三种疾病模型，它们代表了广泛的补体介导的疾病，并对医疗保健和临床具有很高的影响。尽管对血液透析和肾移植的炎症反应（项目2）代表了人工和异物表面引起的补体激活的不同疾病以及终末期肾病的主要并发症，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，具有很强的感染性。使用相关的体外测定、灵敏的仪器方法（核心6）和啮齿动物和非人灵长类动物中的翻译模型，将研究疾病过程与补体触发物和活性的关系，以及与相关途径（例如，TLR）、对下游炎症过程的影响以及调节因子（例如，氧化损伤、感染）。将生成一组不同的强效、经验证、途径特异性和/或靶向补体抑制剂（项目1，核心B），以便于分析每种疾病中涉及的补体途径和过程。该“抑制剂工具箱”包括中心C3抑制剂坎普他汀的类似物，其将用作基准化合物，以及在个体起始、扩增和效应途径中起作用的实体。疗效、药代动力学、给药和靶向特性的优化将由项目2和3的疾病模型的结果和要求指导。与此同时，在这些相关疾病模型中对有前景的和预先验证的候选抑制剂的评估预计将允许快速转化为治疗概念。已建立的模型、方法和P01的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.