Regulation of inflammatory responses by nucleic-acid binding polymers

核酸结合聚合物调节炎症反应

基本信息

批准号：
8254163
负责人：
Eduarta K Holl
金额：
$ 4.92万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254163
关键词：
Affect Agonist American Animal Model Animals Anti-Inflammatory Agents Antidotes Antigen-Antibody Complex Attention Attenuated Autoantibodies Autoimmune Diseases Binding Brain Cell physiology Cells Chemistry Chronic Complex Confocal Microscopy DNA Data Development Disease Disease Progression Disease model Exanthema Family Family member Genes Glomerulonephritis Goals Immune Immune Cell Activation Immune response Individual Infection Inflammation Inflammatory Inflammatory Response Kidney Kidney Failure Knowledge Lead Ligands Long-Term Effects Lupus Lymphatic Diseases Measures Mediating Molecular Mus Nucleic Acid Binding Nucleic Acids Patients Pharmaceutical Preparations Pharmacologic Substance Polymers Prevention Process Production Proteins RNA Receptor Activation Regulation Reporting Research Serum Signal Transduction Skin Small Interfering RNA Splenomegaly Structure Surface Surface Plasmon Resonance Symptoms Systemic Lupus Erythematosus TLR7 gene Technology Testing Therapeutic Therapeutic Agents Toll-like receptors Treatment Efficacy Work aptamer base cell injury chronic autoimmune disease cytokine design human TLR3 protein human TLR7 protein improved in vivo in vivo Model insight lupus prone mice nucleic acid localization pathogen prevent receptor receptor binding

项目摘要

Toll-like receptor (TLR) family members, TLR 3, 7 and 9, have been implicated in initiation and progression of autoimmune disorders such as systemic lupus erythematosus (SLE). These TLRs are often referred to as nucleic acid sensing TLRs based on their ability to recognize DNAs or RNAs produced by pathogens or damaged cells. During SLE progression these receptors are though to recognize self nucleic acids as well as self nucleic acid complexes and contribute to inflammatory cytokine production and subsequent enhancement of serum autoantibody levels. Recent studies have shown that inhibition of one or two nucleic-acid sensing TLRs using receptor antagonists can partially attenuate autoimmune disease progression. For example, inhibition of TLR7 and 9 results in reduced inflammation and glomerulonephritis, a hallmark of SLE. Current therapies are targeting nucleic-acid sensing TLRs as an effective way to control SLE induction and progression. However, these therapies may produce adverse long-term effects on immune responses and block the ability of immune cells to recognize foreign pathogens and adequately control the spread of infection. Thus, the most effective way to block TLR activation would be to control the ability of nucleic acid ligands to bind TLRs. We hypothesize that agents that bind to DNAs and RNAs regardless of their sequence, structure or chemistry might be able to act as molecular scavengers and inhibit nucleic acid-mediated activation of all RNA and DNA sensing TLRs. To test our hypothesis we propose to explore the potential utility of nucleic acid binding polymers as anti-inflammatory agents in the context of SLE. The overall goal of this proposal is to explore the mechanisms by which individual polymers block the ability of immune cells to produce cytokines post TLR activation, as well as determine the ability of these polymers to be used as therapeutic agents in prevention of SLE. Firstly, we will determine whether polymers are capable of blocking inflammatory processes, induced by TLR agonists, without affecting basic immune cell function. Furthermore, we will use two different approaches, cellular localization via confocal microscopy and TLR binding via surface plasmic resonance technology, to define the mechanism of action for the polymers tested. In addition, we will test the ability of polymers to be used as therapeutic agents in ameliorating chronic autoimmune diseases via two studies. First we will test the ability of polymers to block skin inflammation. We will then determine whether polymers are capable of preventing or reversing SLE. The successful completion of this project will provide us with valuable, potent, and well-characterized anti-inflammatory agents, which will block aberrant activation of immune cells during autoimmune disease development and progression.

Toll 样受体 (TLR) 家族成员 TLR 3、7 和 9 与系统性红斑狼疮 (SLE) 等自身免疫性疾病的发生和进展有关。这些 TLR 通常被称为核酸感应 TLR，因为它们能够识别病原体或受损细胞产生的 DNA 或 RNA。在 SLE 进展期间，这些受体被认为能够识别自身核酸以及自身核酸复合物，并有助于炎症细胞因子的产生和随后血清自身抗体水平的增强。最近的研究表明，使用受体拮抗剂抑制一种或两种核酸感应 TLR 可以部分减弱自身免疫性疾病的进展。例如，抑制 TLR7 和 9 可减少炎症和肾小球肾炎（SLE 的一个标志）。目前的疗法以核酸传感 TLR 为目标，将其作为控制 SLE 诱导和进展的有效方法。然而，这些疗法可能会对免疫反应产生不利的长期影响，并阻碍免疫细胞识别外来病原体和充分控制感染传播的能力。因此，阻断 TLR 激活的最有效方法是控制核酸配体结合 TLR 的能力。我们假设，无论 DNA 和 RNA 的序列、结构或化学性质如何，与 DNA 和 RNA 结合的试剂可能能够充当分子清除剂，并抑制核酸介导的所有 RNA 和 DNA 传感 TLR 的激活。为了检验我们的假设，我们建议探索核酸结合聚合物作为 SLE 背景下抗炎剂的潜在效用。该提案的总体目标是探索单个聚合物阻断 TLR 激活后免疫细胞产生细胞因子的能力的机制，以及确定这些聚合物用作预防 SLE 的治疗剂的能力。首先，我们将确定聚合物是否能够阻断 TLR 激动剂诱导的炎症过程，而不影响基本的免疫细胞功能。此外，我们将使用两种不同的方法，即通过共聚焦显微镜进行细胞定位和通过表面等离子体共振技术进行 TLR 结合，来定义所测试聚合物的作用机制。此外，我们将通过两项研究测试聚合物作为治疗剂改善慢性自身免疫性疾病的能力。首先，我们将测试聚合物阻止皮肤炎症的能力。然后我们将确定聚合物是否能够预防或逆转 SLE。该项目的成功完成将为我们提供有价值、有效且特性良好的抗炎药物，这将阻止自身免疫性疾病发生和进展过程中免疫细胞的异常激活。