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）：尽管有40年的时间取得了重大进展，但IgA肾病（Igan）的发病机理仍然未知。大多数（约60％）患有IGAN经历疾病的患者与急性呼吸道或胃肠道疾病有关，这似乎代表了病毒感染。肾脏疾病本身被认为是一种免疫复杂肾小球肾炎的一种形式，但抗原的身份仍然是一个争议的根源，并且机制富含IgA的免疫复合物沉积在肾小球中，并导致肾小球功能障碍是/未知的。特别是，负责IgA结合的特定受体以及将这种结合到细胞反应的途径的特征很差。在实验系统中，具有传染病的免疫小鼠的挑战，而不是非传染病或病毒产物的挑战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地调节了肾小球和肾小球细胞对IgA免疫复合物的结合反应的能力。该提案着重于对双链（DS）RNA的肾小球反应，这是一种病毒感染独特的中间体，与非感染性病毒或病毒产物共享的其他刺激不同。我们的具体目标是：1。确定关键的细胞内途径，病毒感染加剧或增强体内肾小球疾病； 2。评估DSRNA的已知传感器的贡献，以增加对体外IgA免疫复合物的定义负载的关键膜和足细胞反应； 3.阐明了暴露于DSRNA和4的主信号转导途径，该途径介导了对IgA免疫复合物的加强反应和4。确定DSRNA或病毒感染是否通过增加的IgA受体的合成来促进IgA免疫复合物的结合。总体而言，我们将对野生型小鼠或细胞之间IgA免疫复合物的反应和对比反应与在小鼠或具有所选转录因子或受体的靶向遗传缺失的细胞中的细胞中进行比较。这项工作将为Igan的起源以及其他病毒相关的肾小球肾炎（例如与乙型肝炎感染相关）提供机械见解。这项工作对退伍军人的医疗保健产生了潜在的影响，因为这种机械见解可能会指导IGAN新型治疗策略的发展。伊甘（Igan）是一种常见但目前无法治疗的慢性肾脏疾病，会影响退伍军人，尤其是在生命的第二十年和第三十年中的男性。治疗IGAN的新疗法可以降低退伍军人和非退伍军人的透析或肾脏移植的常见原因的发病率，死亡率和治疗成本。公共卫生相关性：与退伍军人的健康有关，这项工作将为IgA肾病的发病机理和进展的机制提供见解，IgA肾病是肾小球肾炎的一种常见形式，影响了退伍军人和铅（约30％的患者）终止阶段肾脏疾病。在第二十年和第三十年的男性中，这种疾病尤为普遍，在积极的军事部署中返回的人群中，这种疾病丰富了。在年轻退伍军人中发起的疾病的慢性性质和进步潜力使该主题与VA高度相关。开发了治疗IgA肾病的新型治疗策略，这种疾病现在没有特定或已建立的有效疗法，可以降低退伍军人和非退伍军人的治疗的发病率，死亡率和治疗成本。例如，根据本文提出的实验的结果，重组干扰素或IFNAR拮抗剂的“关闭标签”使用，现在两者现在都在临床上用于其他条件，最终可能会证明用于治疗Igan。此外，鉴于我们患者人群中丙型肝炎和人类免疫缺陷病毒感染的患病率增加，这项工作对我们的退伍军人来说甚至可能具有更大的价值。