Role of the Complement System in Renal Disease

补体系统在肾脏疾病中的作用

• 批准号: 7921649
• 负责人: RICHARD J. QUIGG
• 金额: $ 31.65万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921649
• 关键词: Abbreviations; Acute Renal Failure with Renal Papillary Necrosis; Affect; Affinity; Anaphylatoxins; Anatomic Sites; Anatomy; Animal Model; Animals; Antibodies; Antigen-Antibody Complex; Apoferritin; Binding; Biological Models; Blood; Blood Cells; Blood Platelets; Bone Marrow; CD46 Antigen; CD55 Antigens; Capillary Endothelial Cell; Cell Culture Techniques; Cells; Cessation of life; Chronic; Clinical; Collection; Complement; Complement 3a; Complement 3b; Complement 5a; Complement Activation; Complement Factor H; Complement Membrane Attack Complex; Complement Receptor; Development; Diffuse; Disease; Disease model; Epithelial; Epithelial Cells; Event; Fc Receptor; Focal glomerulosclerosis; Functional disorder; Funding; Gene Family; Gene Proteins; Glomerular Capillary; Goals; Grant; Human; Immune system; Immunoglobulin G; Infection; Infiltration; Inflammation; Injury; Kidney; Kidney Diseases; Kidney Transplantation; Lead; Leukocytes; Marrow; Mediating; Mediator of activation protein; Membranoproliferative Glomerulonephritis; Membranous Glomerulonephritis; Modeling; Mus; Organ failure; Pathogenesis; Pathway interactions; Patients; Physiological; Plant Roots; Plasma; Play; Population; Process; Production; Proteins; Recombinant Proteins; Research; Research Support; Rodent; Role; Serum Sickness; Side; Site; System; Techniques; Tubular formation; Tumor Necrosis Factor Receptor; United States; Work; acquired immunity; analog; arm; cell injury; complement pathway; complement system; genetic regulatory protein; human disease; in vivo; kidney cell; mouse model; neonatal Fc receptor; pathogen; podocyte; receptor; toll-like receptor 4; urinary

DESCRIPTION (provided by applicant): The collection of plasma and cellular proteins comprising the complement system plays an important role in innate and acquired immunity to infections. Yet, unrestricted or misdirected complement activation can also contribute to human disease states. Oftentimes, such complement activation represents a key early event in disease development. The research supported by this grant over the years has investigated these aspects to understand the role of complement in renal disease. Complement factor H, decay accelerating factor, and complement receptor 1-related protein y (Crry) are responsible for limiting spontaneous, and immune complex- and antibody-mediated complement activation, while the receptors (R) for the C3a and C5a anaphylatoxins transduce many of the effects of this complement activation. As such, the work proposed here will investigate these five proteins and their roles in intrinsic renal endothelial and epithelial cells. In particular, complement-dependent mechanisms that lead to injury of intrinsic renal cells, infiltration of the kidney with extrinsic leukocytes, and ultimately, the development of chronic injury and irreversible organ failure will be examined. This work will be aided by the mouse model systems developed in the past funding period in which there are renal cellular injury and inflammation. Each is reflective of a particular human kidney disease. In addition, each requires a particular combination of abnormal or excessive functioning of C3aR, C5aR, factor H, decay accelerating factor, and Crry, emphasizing their relevancy. Through the use of genetically manipulated mice and recombinant proteins, and the techniques of bone marrow and kidney transplantation to determine effects of these proteins in specific cellular populations, relevant cellular pathways involved in disease pathophysiology will be dissected. Culture systems of these intrinsic renal cells will also be utilized to examine pathways and underlying cellular events that can be attributed to products of complement activation. These will be used in parallel with studies in the experimental animal, with the aim to recapitulate events occurring in vivo using these defined systems. Together, these can provide an unprecedented view of intrinsic events underlying disease pathogenesis that occur in the kidney from complement activation. The proposed work continues our efforts to understand how the complement system in involved in renal disease. Better and more specific therapy for these diseases in a clinical setting can come from this understanding of renal pathophysiology in animal models of human diseases. Kidney disease has become altogether too common in the United States, causing a great deal of illness, inconvenience, and even death. The goal of this work is to understand the root cause of human kidney diseases through the use of animal and cell culture model systems. The information from these studies will be used to determine treatment options for patients suffering from kidney diseases.

描述（由申请人提供）：包含补体系统的血浆和细胞蛋白的收集在先天和获得的感染免疫中起着重要作用。然而，不受限制或误导的补体激活也会导致人类疾病状态。通常，这种补体激活代表了疾病发展中的重要早期事件。多年来，这项赠款支持的研究研究了这些方面，以了解补体在肾脏疾病中的作用。补体因子H，衰减加速因子和补体受体1相关蛋白Y（CRRY）负责限制自发性，以及免疫复合物和抗体介导的补体激活，而C3A和C5A过敏毒素的受体（R）（R）（R）（R）传递了这种补体活化的许多影响。因此，这里提出的工作将研究这五种蛋白质及其在固有的肾脏内皮和上皮细胞中的作用。特别是，将检查导致内在肾细胞损伤的补体依赖性机制，肾脏浸润外在白细胞的渗透，最终将检查慢性损伤和不可逆器官衰竭的发展。这项工作将由在过去的融资期间开发的小鼠模型系统帮助，其中肾细胞损伤和炎症。每个都反映了特定的人类肾脏疾病。此外，每种都需要特定的C3AR，C5AR，因子H，衰减加速因子和crry的异常或过度功能的组合，并强调其相关性。通过使用遗传操纵的小鼠和重组蛋白，以及骨髓和肾脏移植的技术来确定这些蛋白质在特定细胞群体中的影响，将阐明与疾病病理生理有关的相关细胞途径。这些内在肾细胞的培养系统还将用于检查可以归因于补体激活产物的途径和潜在的细胞事件。这些将与实验动物的研究并行使用，目的是使用这些定义的系统概括体内发生的事件。总之，这些可以提供对肾脏中疾病发病机理的内在事件的前所未有的观点，这些事件会因补体激活而发生。拟议的工作继续我们的努力，以了解如何参与肾脏疾病的补体系统。在临床环境中这些疾病的更好，更具体的疗法可能来自对人类疾病动物模型中肾脏病理生理学的理解。肾脏疾病在美国已经变得太普遍了，导致了很多疾病，不便甚至死亡。这项工作的目的是通过使用动物和细胞培养模型系统来了解人类肾脏疾病的根本原因。这些研究的信息将用于确定患有肾脏疾病的患者的治疗选择。