Engineering Polymers to Scavenge DAMPs in Arthritis and Lupus

摘要/工作说明书 我们实验室以前的研究表明，核酸结合聚合物（NABP）， 称为核酸清除剂（NASs），可以抑制由核酸诱导的免疫应答， 狼疮易感小鼠的急性和慢性模型。虽然这些研究表明， NASs作为狼疮的治疗药物，其药理学特性的许多方面都不太理想。 因此，为了推进这种新方法，我们将利用尖端的生物工程策略， 产生新的、生物相容的NABP，用于在体内用作核酸清除剂。最后，建议 研究将结合狼疮患者材料以及动物模型的研究， 核酸DAMP（损伤相关分子模式）反应的基本问题，确定 用于疾病进展和分类的新生物标志物，并阐明 NABP螯合和抑制核酸以防止（或破坏）免疫缺陷的形成。 复合物，从而降低这种DAMP的致病潜力。三个具体目标是 提议： 目的#1：合理地工程化生物相容性核酸清除剂，其具有优化的与 含有核酸的DAMP和相关的DAMP复合物。 目的#2：评价的治疗有效性、安全性、生物分布和生物相容性 在狼疮小鼠模型中含有核酸清除剂的可溶性和纳米颗粒 表现为肾脏、皮肤和关节炎症状。 目的#3：阐明核酸清除剂抵消 在小鼠和患者中激活炎性细胞 样品 成功完成拟议的研究将为一种新的临床开发奠定基础。 是一类安全有效的抗炎药，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.