Complement-mediated injury of the kidney: New mechanisms and novel therapies

补体介导的肾脏损伤：新机制和新疗法

• 批准号: 10583769
• 负责人: Joshua M Thurman
• 金额: $ 46.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583769
• 关键词: Affect; Affinity; Alternative Complement Pathway; Annexins; Antigen-Antibody Complex; Autoantibodies; Autoimmune Responses; B-Lymphocytes; Basement membrane; Binding; Cells; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Factor B; Complement Factor D; Complement Factor H; Complement Inactivators; Consumption; Defect; Deposition; Drug Targeting; Equilibrium; Event; Exposure to; Feedback; Genes; Glomerular Capillary; Glomerulonephritis; Grant; Hemolytic-Uremic Syndrome; IGA Glomerulonephritis; Immune; Immunity; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Injury; Injury to Kidney; Kidney; Kidney Diseases; Kidney Failure; Ligation; Location; Lupus Nephritis; Mediating; Membranous Glomerulonephritis; Molecular; Mutation; Myeloid Cells; Organ; Pathologic Processes; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Plasma; Predisposition; Probability; Process; Production; Protein Engineering; Proteins; Public Health; Publishing; Renal glomerular disease; Research; Site; Surface; T-Lymphocyte; Testing; Therapeutic Agents; Tissues; Work; adaptive immune response; adaptive immunity; antagonist; blocking factor; complement system; design; experimental study; glomerular basement membrane; in vivo Model; infection risk; novel; novel strategies; novel therapeutics; prevent; protective pathway; receptor

The alternative pathway of complement contributes to a wide range of glomerular diseases. Factor H is the main regulator of this innate immune cascade. Although some patients with kidney disease have underlying defects in factor H, complete deficiency of the protein is quite rare. It is not clear why kidney is so frequently the target of alternative pathway-mediated injury. One possible explanation is that endogenous proteins can function as factor H antagonists, effectively creating microenvironments locally deficient in the regulator. The factor H related proteins (FHRs), for example, antagonize binding of factor H to tissue surfaces, including the glomerular basement membrane (GBM). We have also discovered that another class of proteins - the annexins - act as factor H antagonists on kidney surfaces. Although the FHRs and annexins probably block factor H from binding other tissues in the body, the high concentration of alternative pathway proteins within the glomerular capillaries causes preferential activation at this location. Based on these findings, the primary hypothesis of this grant is that is that the GBM is uniquely susceptible to alternative pathway activation because the dysregulatory proteins (FHRs and annexins) effectively block factor H from binding this surface, yet it is simultaneously exposed to high concentrations of activating proteins. Alternative pathway activation within the glomerulus generates C3a and C5a, which ligate receptors on resident myeloid cells and create an inflammatory milieux within the kidney. Complement fragments generated in the kidney also stimulate T cells and B cells systemically. To test this hypothesis, the following specific aims will be pursued. Aim 1) Characterize the effects of dysregulatory proteins in the kidney. We will use in vitro and in vivo models to explore the molecular mechanisms that cause alternative pathway activation in the kidney. Aim 2. Examine the downstream effects of AP activation in the kidney. In this aim we will explore the downstream effects of glomerular complement activation on cells throughout the kidney. We will also examine whether complement activation in the glomeruli affects the adaptive immune response systemically. This could represent a mechanism by which inflammation in the kidney increases production of autoantibodies, creating a positive feed-back loop. Aim 3. Test novel strategies for blocking complement activation in the kidney. In this aim we will test the ability of novel engineered proteins to reverse alternative pathway dysregulation in the kidney. The project is expected to provide an overarching explanation for why the kidney - among all the organs - is so uniquely susceptible to alternative pathway-mediated injury. These studies will also test strategies for specifically blocking kidney inflammation. By targeting the underlying molecular triggers of complement activation in the kidney, drugs can be designed to inhibit these pathologic processes without blocking complement-mediated immunity systemically. This approach is expected to be both more effective and safer than currently available treatments.

补体的旁路途径导致广泛的肾小球疾病。因子H是 先天免疫级联反应的主要调节者虽然一些肾病患者有潜在的 由于H因子的缺陷，蛋白质的完全缺乏是相当罕见的。目前尚不清楚为什么肾脏如此频繁地 替代途径介导的损伤的靶点。一种可能的解释是内源性蛋白质可以 作为H因子拮抗剂发挥作用，有效地产生调节剂局部缺乏的微环境。的 例如，因子H相关蛋白（FHR）拮抗因子H与组织表面的结合，包括 肾小球基底膜（GBM）。我们还发现，另一类蛋白质-- 膜联蛋白-作为肾脏表面的H因子拮抗剂。尽管FHR和膜联蛋白可能阻止 H因子与体内其他组织结合，体内高浓度的旁路途径蛋白质 肾小球毛细血管在该位置引起优先激活。根据这些发现，主要 这项研究的假设是，GBM是唯一易受旁路途径激活的 因为失调蛋白（FHR和膜联蛋白）有效地阻止因子H结合该表面， 但它同时暴露于高浓度的活化蛋白。替代途径活化 在肾小球内产生C3 a和C5 a，它们连接驻留的髓样细胞上的受体， 肾脏内的炎症环境。肾脏中产生的补体片段也刺激T细胞 细胞和B细胞。为了检验这一假设，将追求以下具体目标。目标1） 描述肾脏中失调蛋白的影响。我们将使用体外和体内模型， 探索导致肾脏替代途径激活的分子机制。目标2.审查 肾脏中AP激活的下游效应。在这个目标中，我们将探讨的下游影响， 肾小球补体激活整个肾脏的细胞。我们还将研究 肾小球中的补体激活系统性地影响适应性免疫应答。这可能 代表肾脏炎症增加自身抗体产生的机制， 形成一个正反馈循环。目标3.测试阻断补体激活的新策略， 肾在这个目标中，我们将测试新的工程蛋白质逆转旁路途径的能力。 肾功能失调该项目预计将提供一个全面的解释，为什么 肾脏-在所有器官中-是如此独特地易受替代途径介导的损伤。这些 研究还将测试专门阻断肾脏炎症的策略。通过瞄准潜在的 肾脏中补体激活的分子触发剂，可以设计药物来抑制这些病理性的 过程而不阻断补体介导的免疫系统。预计这一方法将在 比现有的治疗方法更有效、更安全。