Engineering Polymers to Scavenge DAMPs in Arthritis and Lupus

工程聚合物可清除关节炎和狼疮中的 DAMP

• 批准号: 10470805
• 负责人: KAM W LEONG
• 金额: $ 65.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470805
• 关键词: Acids; Acute; Address; American; Animal Model; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Antigen-Antibody Complex; Antinuclear Antibodies; Arthralgia; Arthritis; Autoimmune; Autoimmune Diseases; Binding; Biocompatible Materials; Biodistribution; Biological Markers; Biomedical Engineering; Blood; Cell Nucleus; Cells; Cessation of life; Characteristics; Chemistry; Chronic; Clinical; Complex; Cutaneous; DNA; Deposition; Diagnosis; Digestion; Disease; Disease Progression; Drug Design; Elements; Engineering; Event; Family; Human; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Injury; Interferons; Joints; Kidney; Laboratories; Lead; Lupus; Lupus Nephritis; Mediating; Modeling; Molecular; Molecular Structure; Morbidity - disease rate; Mus; Nuclear; Nuclear Antigens; Nucleic Acid Binding; Nucleic Acids; Pathogenesis; Pathogenicity; Patients; Pattern; Pattern recognition receptor; Pharmacology; Polymers; Principal Investigator; Process; Production; Prognosis; Property; Proteins; RNA; RNA-Binding Proteins; Reagent; Research; Rheumatoid Arthritis; Ribonucleases; Role; Safety; Sampling; Serology; Skin; Source; Staging; Structure; Study models; Systemic Lupus Erythematosus; TLR3 gene; Testing; Therapeutic Agents; Therapeutic Effect; Time; Toll-like receptors; Toxic effect; Transfection; Translational Research; Treatment Efficacy; Work; biomaterial compatibility; clinical development; clinically significant; cytokine; disease classification; extracellular; in vivo; lupus prone mice; lupus-like; mortality; mouse model; nanoparticle; novel; novel marker; novel strategies; particle; prevent; protein complex; response; sensor; therapeutic evaluation; Acids; Acute; Address; American; Animal Model; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Antigen-Antibody Complex; Antinuclear Antibodies; Arthralgia; Arthritis; Autoimmune; Autoimmune Diseases; Binding; Biocompatible Materials; Biodistribution; Biological Markers; Biomedical Engineering; Blood; Cell Nucleus; Cells; Cessation of life; Characteristics; Chemistry; Chronic; Clinical; Complex; Cutaneous; DNA; Deposition; Diagnosis; Digestion; Disease; Disease Progression; Drug Design; Elements; Engineering; Event; Family; Human; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Injury; Interferons; Joints; Kidney; Laboratories; Lead; Lupus; Lupus Nephritis; Mediating; Modeling; Molecular; Molecular Structure; Morbidity - disease rate; Mus; Nuclear; Nuclear Antigens; Nucleic Acid Binding; Nucleic Acids; Pathogenesis; Pathogenicity; Patients; Pattern; Pattern recognition receptor; Pharmacology; Polymers; Principal Investigator; Process; Production; Prognosis; Property; Proteins; RNA; RNA-Binding Proteins; Reagent; Research; Rheumatoid Arthritis; Ribonucleases; Role; Safety; Sampling; Serology; Skin; Source; Staging; Structure; Study models; Systemic Lupus Erythematosus; TLR3 gene; Testing; Therapeutic Agents; Therapeutic Effect; Time; Toll-like receptors; Toxic effect; Transfection; Translational Research; Treatment Efficacy; Work; biomaterial compatibility; clinical development; clinically significant; cytokine; disease classification; extracellular; in vivo; lupus prone mice; lupus-like; mortality; mouse model; nanoparticle; novel; novel marker; novel strategies; particle; prevent; protein complex; response; sensor; therapeutic evaluation

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.

摘要/工作陈述 我们实验室的先前研究表明，核酸结合聚合物（NABPS）也 称为核酸清除剂（NASS），可以抑制核酸引起的免疫反应 狼疮小鼠的急性和慢性模型。尽管这些研究表明 NASS作为狼疮的疗法，其药理特性的许多方面都不理想。 因此，要推进这种新颖的方法，我们将利用最先进的生物工程策略 创建新型的生物相容性NABP，用于体内用作核酸清除剂。最后，提议 研究将与狼疮患者材料以及动物模型一起进行研究以解决 核酸湿（损伤相关的分子模式）的基本问题，识别 疾病进展和分类的新型生物标志物，并阐明了该机制 NABPS隔离和清除核酸，以防止（或破坏）免疫的形成 复合物，从而降低此类潮湿的致病潜力。三个具体目标是 建议的： 目标＃1：合理地工程师生物相容性，具有优化结合的核酸清除剂 含核酸的潮湿和相关的潮湿复合物。 目标＃2：评估治疗功效，安全性，生物分布和生物相容性 狼疮小鼠模型中含有核酸清除剂的可溶性和纳米颗粒 表现出肾脏，皮肤和关节炎的表现。 目标＃3：阐明核酸清除剂抵消能力的机制 含核酸的潮湿，激活小鼠和患者的炎性细胞 样品。 成功完成的研究将为新颖的临床发展奠定阶段 狼疮和狼疮性炎患者的一类安全和有效的抗炎剂。