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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

基本信息

批准号：
10220851
负责人：
KAM W LEONG
金额：
$ 64.72万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220851
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

项目摘要

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/工作说明书我们实验室之前的研究表明，核酸结合聚合物 (NABP) 称为核酸清除剂（NAS），可以抑制核酸诱导的免疫反应易患狼疮的小鼠的急性和慢性模型。虽然这些研究表明了潜在的效用 NAS 作为狼疮的治疗药物，其药理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创建新型、生物相容性 NABP，作为体内核酸清除剂使用。最后，提出的研究将结合狼疮患者材料和动物模型的研究来解决核酸 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型生物标志物，并阐明其机制 NABP 隔离和清除核酸以防止（或破坏）免疫细胞的形成复合物，从而降低此类 DAMP 的致病潜力。三个具体目标是建议的：目标#1：合理设计具有优化结合能力的生物相容性核酸清除剂含有核酸的 DAMP 和相关的 DAMP 复合物。目标#2：评估治疗效果、安全性、生物分布和生物相容性狼疮小鼠模型中含有可溶性和纳米颗粒的核酸清除剂显示肾脏、皮肤和关节炎表现。目标#3：阐明核酸清除剂抵消这种能力的机制含有核酸的 DAMP 激活小鼠和患者体内的炎症细胞样品。成功完成拟议的研究将为新型药物的临床开发奠定基础用于狼疮和狼疮关节炎患者的一类安全有效的抗炎药。