Engineering Polymers to Scavenge DAMPs in Arthritis and Lupus

摘要/工作说明 我们实验室以前的研究表明，核酸结合聚合物(NABP)也 被称为核酸清道夫(NASS)，能抑制核酸诱导的免疫反应 狼疮易感小鼠的急性和慢性模型。虽然这些研究表明， NASS作为治疗狼疮的药物，其许多方面的药理作用并不理想。 因此，为了推进这一新方法，我们将利用尖端生物工程策略来 创造新的、生物相容的NABP，用于体内用作核酸清除剂。最后，提出了 研究将结合对狼疮患者材料和动物模型的研究，以解决 核酸DAMP(损伤相关分子模式)反应的基本问题，识别 疾病进展和分类的新生物标志物及其作用机制(S) NABPs隔离和清除核酸以防止(或干扰)免疫的形成 因此可以降低这种湿气的致病潜力。三个具体目标是 建议： 目标1：合理设计生物相容的核酸清除剂，并优化结合 含核酸的湿气及其相关的湿气络合物。 目的#2：评价阿司匹林的疗效、安全性、生物分布和生物相容性。 含核酸清除剂的可溶性和纳米微粒在狼疮小鼠模型中的应用 表现为肾脏、皮肤和关节炎的患者。 目的#3：阐明核酸清除剂中和能力的机制(S) 在小鼠和患者体内激活炎症细胞的含有核酸的湿润物质 样本。 拟议研究的成功完成将为新药的临床开发奠定基础 一类安全有效的抗炎药，适用于狼疮和狼疮关节炎患者。

Abstract/Statement of Work Previous studies from our laboratories have indicated that nucleic acid binding polymers (NABPs), also termed nuclear acid scavengers (NASs), can inhibit immune responses induced by nucleic acids in both acute and chronic models in lupus prone mice. While these studies indicate the potential utility of NASs as a therapy for lupus, many aspects of their pharmacologic properties are less than ideal. Therefore, to advance this novel approach, we will utilize cutting edge bioengineering strategies to create novel, biocompatible NABPs for in vivo use as nucleic acid scavengers. Finally, the proposed research will incorporate studies with lupus patient material as well as animal models to address fundamental issues on nucleic acid DAMP (Damage Associated Molecular Pattern) responses, identify novel biomarkers for disease progression and classification and elucidate the mechanism(s) by which NABPs sequester and scavenge nucleic acids to prevent (or disrupt) the formation of immune complexes and thereby reduce the pathogenic potential of such DAMPs. Three specific aims are proposed: Aim #1: To rationally engineer biocompatible, nucleic acid scavengers with optimized binding to nucleic acid-containing DAMPs and associated DAMP complexes. Aim #2: To evaluate the therapeutic efficacy, safety, biodistribution and biocompatibility of soluble and nanoparticle containing nucleic acid scavengers in mouse models of lupus that display renal, cutaneous and arthritic manifestations. Aim #3: To elucidate the mechanism(s) by which nucleic acid scavengers counteract the ability of nucleic acid-containing DAMPs to activate inflammatory cells in mice and in patient samples. Successful completion of the studies proposed will set the stage for the clinical development of a novel class of safe and potent anti-inflammatory agents for lupus and lupus-arthritis patients.