Role of innate responses to viruses in the genesis of IgA Nephropathy

对病毒的先天反应在 IgA 肾病发生中的作用

基本信息

批准号：
8262615
负责人：
STEVEN N EMANCIPATOR
金额：
--
依托单位：
LOUIS STOKES CLEVELAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8262615
关键词：
Accounting Acute Affect Animal Model Antibody Formation Antigen-Antibody Complex Antigens Binding Cell physiology Cells Chronic Chronic Kidney Failure Clinical Data Deposition Development Dialysis procedure Disease Double-Stranded RNA End stage renal failure Event Exhibits Exposure to Functional disorder Genetic Glomerular Mesangial Cell Glomerulonephritis HIV Health Healthcare Hepatitis C IFNAR1 gene IgA receptor Immune Immune Complex Glomerulonephritis Immune response Immunity Immunization Immunoglobulin A In Vitro Individual Infection Intravenous Kidney Kidney Diseases Kidney Transplantation Label Lead Life Link Measurable Mediating Military Personnel Minority Morbidity - disease rate Mucosal Immunity Mucous Membrane Mus Nature Nephritis Outcome Parainfluenza Pathogenesis Pathway interactions Patients Penetration Population Prevalence Publishing Recombinant Interferon Renal glomerular disease Reporting Respiratory System Respiratory tract structure Role Route Sendai virus Signal Transduction Pathway Source Stimulus System Testing Treatment Cost Veterans Viral Virion Virus Virus Diseases Virus Replication Wild Type Mouse Work chemokine common treatment cytokine effective therapy experience gastrointestinal glomerular function in vivo insight macrophage male mesangial cell mortality mouse model novel novel therapeutics parainfluenza virus pathogen patient population podocyte public health relevance receptor research study respiratory response sensor social

项目摘要

DESCRIPTION (provided by applicant): Despite significant progress over 40 years, the pathogenesis of IgA nephropathy (IgAN) remains unknown. A majority (~60%) of patients with IgAN experience disease exacerbations associated with acute respiratory or gastrointestinal illness that appears to represent viral infection. The renal disease itself is considered to be a form of immune complex glomerulo- nephritis, but the identity of the antigen remains a source of controversy, and the mechanism(s) whereby the IgA-rich immune complexes deposit in the glomeruli and lead to glomerular dysfunction is/are unknown. Particularly, the specific receptor(s) responsible for IgA binding and the pathways that transduce such binding to cellular responses are poorly characterized. In experimental systems, challenge of immune mice with infectious virus, but not with non- infectious virus or viral products, leads to altered glomerular function. We hypothesize that innate immune responses to replication of viruses modulate, directly or indirectly, the capacity of glomeruli and mesangial cells to respond to binding of IgA immune complexes. This proposal focuses on glomerular responses to double-stranded (ds) RNA, an intermediate unique to viral infection that is distinct from other stimuli that are shared by noninfectious virus or viral products. Our Specific Objectives are to: 1. identify the key intracellular pathway whereby viral infection exacerbates or intensifies glomerular disease in vivo; 2. evaluate the contribution of the known sensor(s) of dsRNA to increase the key mesangial and podocyte responses to a defined load of IgA immune complexes in vitro; 3. elucidate the principal signal transduction pathway that mediates intensified cellular responses to IgA immune complexes after exposure to dsRNA and 4. determine whether dsRNA or viral infection promotes binding of IgA immune complexes via increased synthesis of IgA receptors. Overall, we will compare and contrast responses to IgA immune complexes between wild type mice or cells to those in mice or cells bearing targeted genetic deletions of selected transcriptional factors or receptors. This work will offer mechanistic insights to the genesis of IgAN, and perhaps to other virally-associated glomerulo- nephritis (e.g. that associated with hepatitis C infection). This work has a potential impact on Veterans' health care, because such mechanistic insights might guide development of novel therapeutic strategies for IgAN. IgAN is a common but currently poorly treatable chronic kidney disease that affects Veterans, especially males in their second and third decades of life. New therapies to treat IgAN can reduce morbidity, mortality and costs of treatment of this common cause of dialysis or renal transplantation in Veterans and non-Veterans alike. PUBLIC HEALTH RELEVANCE: Relevance to Veterans' Health This work will provide insight to the mechanisms of pathogenesis and progression of IgA nephropathy, a common form of glomerulonephritis that affects Veterans and leads (in ~30% of patients) to end stage renal disease. The disease is especially prevalent in males in the second and third decades of life, a population that is enriched among those returning from active military deployment. The chronic nature and progressive potential of a disease that initiates in young Veterans makes this topic highly relevant to the VA. Development of novel therapeutic strategies to treat IgA nephropathy, a disease for which no specific or established effective therapy now exists, can reduce morbidity, mortality and costs of treatment in Veterans and non-Veterans alike. For example, depending on the outcome of the experiments proposed herein, "off label" uses of recombinant interferon or IFNAR antagonists, both now used clinically for other conditions, might ultimately prove salutary for treatment of IgAN. Furthermore, given an increased prevalence of both hepatitis C and human immunodeficiency virus infections in our patient population, this work may be of even wider value to our Veterans.

描述（由申请人提供）：尽管 40 年来取得了重大进展，但 IgA 肾病 (IgAN) 的发病机制仍然未知。大多数 (~60%) IgAN 患者会出现与急性呼吸道或胃肠道疾病相关的疾病恶化，这些疾病似乎代表病毒感染。肾脏疾病本身被认为是免疫复合物肾小球肾炎的一种形式，但抗原的身份仍然存在争议，而富含 IgA 的免疫复合物沉积在肾小球中并导致肾小球肾炎的机制仍然存在争议。功能障碍未知。特别是，负责 IgA 结合的特定受体以及将这种结合转导至细胞反应的途径的特征还很不清楚。在实验系统中，用感染性病毒而非非感染性病毒或病毒产物攻击免疫小鼠会导致肾小球功能改变。我们假设对病毒复制的先天免疫反应直接或间接调节肾小球和系膜细胞对 IgA 免疫复合物结合作出反应的能力。该提案重点关注肾小球对双链 (ds) RNA 的反应，双链 RNA 是病毒感染特有的中间体，与非感染性病毒或病毒产物共有的其他刺激不同。我们的具体目标是： 1. 确定病毒感染在体内加剧或强化肾小球疾病的关键细胞内途径； 2. 评估已知的 dsRNA 传感器对增加关键系膜和足细胞对体外确定的 IgA 免疫复合物负载的反应的贡献； 3. 阐明暴露于 dsRNA 后介导增强细胞对 IgA 免疫复合物反应的主要信号转导途径，以及 4. 确定 dsRNA 或病毒感染是否通过增加 IgA 受体的合成来促进 IgA 免疫复合物的结合。总的来说，我们将比较和对比野生型小鼠或细胞与携带选定转录因子或受体的靶向遗传缺失的小鼠或细胞对 IgA 免疫复合物的反应。这项工作将为 IgAN 的起源提供机制见解，或许还为其他病毒相关的肾小球肾炎（例如与丙型肝炎感染相关的肾小球肾炎）提供机制见解。这项工作对退伍军人的医疗保健具有潜在影响，因为这种机制见解可能会指导 IgAN 新型治疗策略的开发。 IgAN 是一种常见但目前治疗效果不佳的慢性肾脏疾病，影响退伍军人，尤其是二十多岁和三十岁的男性。治疗 IgAN 的新疗法可以降低退伍军人和非退伍军人的这种常见透析或肾移植病因的发病率、死亡率和治疗费用。公共卫生相关性：与退伍军人健康的相关性这项工作将深入了解 IgA 肾病的发病机制和进展机制，IgA 肾病是肾小球肾炎的一种常见形式，影响退伍军人并导致（约 30% 的患者）发展为终末期肾病。这种疾病在二十岁和三十岁的男性中尤其流行，这一人群在从现役部队返回的人中更为丰富。年轻退伍军人发病的疾病的慢性性质和进展潜力使得该主题与退伍军人管理局高度相关。 IgA 肾病是一种目前尚无特异性或既定有效疗法的疾病，开发新的治疗策略可以降低退伍军人和非退伍军人的发病率、死亡率和治疗费用。例如，根据本文提出的实验结果，重组干扰素或IFNAR拮抗剂的“标签外”使用（两者现在都在临床上用于其他病症）可能最终证明对IgAN的治疗有益。此外，鉴于我们的患者群体中丙型肝炎和人类免疫缺陷病毒感染的患病率不断增加，这项工作可能对我们的退伍军人具有更广泛的价值。