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Defining glomerulus-homing peptides for targeted drug delivery in lupus nephritis

定义用于狼疮性肾炎靶向药物递送的肾小球归巢肽

基本信息

批准号：
8787075
负责人：
KAMAL D MOUDGIL
金额：
$ 23.03万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-20 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8787075
关键词：
Address Adjuvant Arthritis Adverse effects Adverse reactions Affect Alanine Animal Model Antibodies Area Arginine Arthritis Asparagine Aspartate Autoimmune Diseases Autoimmune Process Bacteriophages Binding Blood Circulation Blood Vessels Cells Characteristics Chronic Clinical Code Collaborations Cyclophosphamide DBA/2 Mouse Detection Disease Disease model Drug Delivery Systems Drug Targeting Encapsulated Endothelial Cells Experimental Models Glutamine Glycine Goals Health Heterogeneity Home environment Homing Human Individual Inflammation Inflammation Mediators Injection of therapeutic agent Integrins Joints Kidney Kidney Glomerulus Knowledge Libraries Ligands Liposomes Lupus Lupus Nephritis Lymphocyte Lysine Mediating Methodology Methods Modeling Mus Normal tissue morphology Organ Parents Pathogenesis Peptide Phage Display Library Peptides Phage Display Pharmaceutical Preparations Physiological Process Proteins Publishing RGD (sequence)Rattus Reporting Research Personnel Surface System Systemic Lupus Erythematosus T-Lymphocyte Technology Testing Therapeutic Agents Tissues Toxic effect Translational Research Tumor Biology United States National Academy of Sciences Vascular Endothelial Cell Vascular Endothelium Vesicle Work angiogenesis autoreactive T cell base design graft vs host disease in vivo innovation member migration molecular marker mycophenolate mofetil nanoparticle neoplasm immunotherapy neoplastic cell novel novel therapeutic intervention prevent receptor receptor binding response risk benefit ratio screening systemic autoimmune disease trafficking treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE, or lupus) is a chronic debilitating systemic autoimmune disease involving inflammation and damage to the renal glomeruli and other tissues. Both autoreactive T cells and antibodies are involved in mediating the pathogenic effector responses in lupus. Two of the main challenges for researchers working in the field of SLE are - 1) to define the underlying mechanisms that render the renal glomeruli highly prone to an autoimmune attack, and 2) to devise novel ways to direct the orally-administered or injected drugs primarily to inflamed glomeruli to enhance their efficacy while minimizing adverse effects. We hypothesize that the vascular endothelium of the renal glomeruli is characterized by unique molecular markers that facilitate both selective migration of the pathogenic T cells into the target organ (the kidney) as well as enhanced interaction with the inducers/mediators of inflammation and tissue damage. In collaboration with Dr. Erkki Ruoslahti (Sanford-Burnham, La Jolla & UCSB, CA; member, National Academy of Sciences), we recently completed and published (PNAS 2011, 108: 12857) a study of the synovial vasculature in the rat adjuvant arthritis model. The objective of that study was to identify unique joint-specific vascular endothelial markers using an innovative approach of in vivo enrichment of clones from a phage peptide-display library. This approach was pioneered by Dr. Ruoslahti, who has developed the concept of vascular 'address molecules' or 'zip codes' and has extensively applied it to the areas of tumor biology and tumor immunotherapy. The advantage of the phage system for detection of tissue-specific markers is that there is no a priori bias in predicting the ligand in the vascular endothelial or other cells. In addition, unlike antibodies, the phage- displayed peptides interact with the functional domain of the target molecule. We propose that the vascular endothelial cells of the inflamed renal glomeruli are characterized by unique molecular markers, and that the targeting of drugs via one or more of these markers would downregulate inflammation and tissue damage in the kidney without undue adverse reactions or systemic toxicity. The aims of our study based on two animal models of lupus, one induced and other spontaneous, are as follows: Aim 1. To identify unique 'address molecules' for the vascular endothelium of the target organ (the inflamed renal glomeruli) in mice with lupus using the in vivo screening of a phage peptide-display library. Aim 2. To use the phage-encoded peptides for targeted drug delivery into the inflamed renal glomeruli to control inflammation and tissue damage in the kidney. We believe that the results of this study would advance our understanding of the pathogenesis of lupus, and help designing novel therapeutic approaches for human lupus via translational research.

描述（由申请人提供）：系统性红斑狼疮（SLE，或狼疮）是一种慢性衰弱性系统性自身免疫性疾病，涉及肾小球和其他组织的炎症和损伤。自身反应性 T 细胞和抗体都参与介导狼疮的致病效应反应。 SLE 领域的研究人员面临的两个主要挑战是：1) 确定肾小球极易遭受自身免疫攻击的潜在机制，2) 设计新方法将口服或注射药物主要引导至发炎的肾小球，以增强其疗效同时最大限度地减少不利影响。我们假设肾小球的血管内皮具有独特的分子标记，可以促进致病性 T 细胞选择性迁移到靶器官（肾脏），并增强与炎症和组织损伤的诱导剂/介质的相互作用。我们与 Erkki Ruoslahti 博士（加利福尼亚州拉霍亚桑福德伯纳姆和加州大学圣巴巴拉分校；美国国家科学院院士）合作，最近完成并发表了 (PNAS 2011, 108: 12857) 大鼠佐剂关节炎模型滑膜脉管系统的研究。该研究的目的是利用噬菌体肽展示库中克隆的体内富集创新方法来鉴定独特的关节特异性血管内皮标记物。这种方法由 Ruoslahti 博士首创，他提出了血管“地址分子”或“邮政编码”的概念，并将其广泛应用于肿瘤生物学和肿瘤免疫治疗领域。噬菌体系统检测组织特异性标记物的优点是在预测组织特异性标记物时不存在先验偏差。血管内皮细胞或其他细胞中的配体。此外，与抗体不同，噬菌体展示的肽与靶分子的功能域相互作用。我们认为，发炎的肾小球的血管内皮细胞具有独特的分子标记物，并且通过一种或多种这些标记物靶向药物将下调肾脏的炎症和组织损伤，而不会产生过度的不良反应或全身毒性。我们基于两种狼疮动物模型（一种诱导的和另一种自发的）的研究目的如下：目的 1. 使用噬菌体肽展示文库的体内筛选，识别狼疮小鼠靶器官（发炎的肾小球）血管内皮的独特“地址分子”。目标 2. 使用噬菌体编码的肽将靶向药物递送到发炎的肾小球中，以控制肾脏中的炎症和组织损伤。我们相信，这项研究的结果将增进我们对狼疮发病机制的理解，并有助于通过转化研究设计人类狼疮的新治疗方法。