Complement in inflammatory diseases: mechanisms & therapeutic modulation

炎症性疾病中的补体：机制

• 批准号: 8850372
• 负责人: JOHN D LAMBRIS
• 金额: $ 192.15万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850372
• 关键词: Accounting; Acute; Adverse reactions; Affect; Benchmarking; Biochemical; Biocompatible Materials; Biological Assay; Cells; Characteristics; Chronic; Clinic; Clinical; Coagulation Process; Communities; Complement; Complement Activation; Complement Inactivators; Development; Dialysis procedure; Disease; Disease model; Dissection; Drug Kinetics; Drug Targeting; Eating; End stage renal failure; Ensure; Equilibrium; Evaluation; Future; Generations; Graft Rejection; Health; Healthcare; Hemodialysis; Homeostasis; Human; Immune; Immune System Diseases; Immune response; Immunologic Surveillance; In Vitro; Individual; Infection; Inflammation; Inflammatory; Intervention; Kidney Transplantation; Lead; Left; Mediating; Methods; Modeling; Organ; Oxidative Stress; Pathway interactions; Patients; Pattern; Perception; Periodontitis; Physiological; Positioning Attribute; Post-Translational Protein Processing; Primate Diseases; Process; Production; Property; Proteomics; Reaction; Recruitment Activity; Reperfusion Injury; Research; Rewards; Rodent; Role; Sampling; Severities; Shapes; Solutions; Specificity; Stress; Surface; System; Therapeutic; Therapeutic Intervention; Time; Tissues; Toll-like receptors; Translations; Transplantation; Triage; analog; base; cell type; clinical effect; complement pathway; complement system; compstatin; holistic approach; improved; in vitro Assay; in vivo; inhibitor/antagonist; microbial; mouse model; nonhuman primate; novel therapeutics; oxidative damage; pathogen; prevent; programs; research study; response; therapeutic target

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.

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，但促成因素可能是不同的。近年来，补体系统与越来越多的炎症条件有关，包括急性和慢性组织炎症，对生物材料的不良反应以及移植排斥反应。显然，对宿主细胞上过度或不足控制的补体激活可能会导致免疫失衡，从而加剧了诸如氧化应激或感染的因素，可能会在补体，炎症和组织损伤之间加剧恶性循环。结果，对补体的治疗调节是对炎症过程上游抑制的有吸引力的靶标，但需要深入了解基本过程，识别奖励目标以及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中补体参与的共同和独特的分母，并开放途径，以改善治疗策略。为此，将彻底研究三种代表广泛补体介质疾病的疾病模型，并对医疗保健产生很高的影响。尽管对血液透析和肾脏移植的炎症反应（项目2）代表了人造和外国表面的补体激活的不同疾病，以及末期肾脏疾病的重大并发症，牙周炎（项目3）是一种新兴的局部组织炎症模型，具有强烈的感染成分的局部组织炎症模型。使用相关的体外测定，灵敏的仪器方法（核心6）以及啮齿动物和非人类灵长类动物中的翻译模型，将研究疾病过程，与补体触发器和活动有关，以及相关途径（例如TLR），对下游炎症过程和下游炎症过程的影响，以及对模块化损害的影响（例如，氧化因子的影响（例如，TL​​R）。将生成各种有效，经过验证，途径特异性和/或靶向补体抑制剂（项目1，核心B），允许解剖每种疾病中涉及的补体途径和过程。该“抑制剂工具箱”包括中央C3抑制剂Compstatin的类似物，该类似物将用作基准化合物，以及作用于单个启动，扩增和效应子途径的实体。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进行指导。与此同时，在此类相关疾病模型中对有希望和预估计的抑制剂候选者的评估有望快速地转化为治疗概念。该P01的既定模型，方法和抑制剂可以轻松地应用于未来的疾病研究中。因此，该P01将对与补体相关疾病的阐明和管理产生很大的影响，并使患者和研究界受益。