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Novel Protease-Activatable Tracers for Targeted Imaging of Chemerin Receptor in Inflammation

用于炎症中凯莫瑞受体靶向成像的新型蛋白酶激活示踪剂

基本信息

批准号：
9892465
负责人：
Sina Tavakoli
金额：
$ 19.56万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892465
关键词：
Address Affinity Amino Acids Animal Model Binding Biological Blood Circulation C-terminal CMKLR1 gene Cardiovascular Diseases Cathepsins Cells Chelating Agents Chemotactic Factors Chemotaxis Induction Chronic Cleaved cell Colitis Demyelinating Diseases Dendritic Cells Development Disease Disease Progression Early Diagnosis Early identification Elastases Freund&apos s Adjuvant G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Goals Histologic Human Immune Immunomodulators Inflammation Inflammatory Kinetics Label Lead Ligands Mediating Modification Monitor Mus N-terminal Natural Killer Cells Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patient Monitoring Penetrance Penetration Peptide Hydrolases Peptides Plasma Plasmin Play Pneumonia Polyvinyl Alcohol Porifera Process Proteins Pulmonary Inflammation Radiolabeled Regulation Reporting Risk stratification Role Serum Signal Transduction Site Specificity Sterility Structure Time Tissues Tracer Translations Validation Vertebrates base body system chemokine chemokine receptor clinical practice design disorder risk extracellular fluorodeoxyglucose imaging approach imaging probe immunoregulation implantation improved in vivo in vivo imaging in vivo monitoring independency indexing innovation macrophage molecular imaging monocyte mouse model nanomolar novel patient stratification precision medicine prototype radiotracer receptor recruit response subcutaneous targeted imaging uptake

项目摘要

Novel Protease-Activatable Chemerin-Derived Tracers for Molecular Imaging of Inflammation ABSTRACT Molecular imaging of inflammation allows for early identification of the pathogenic processes in a wide range of diseases and may lead to improved risk stratification of patients and monitoring the progression of disease or response to therapy. Thus, it represents a major driver of Precision Medicine, particularly with the growing development and applications of novel immunomodulatory therapeutics. However, limitations of the current molecular imaging tracers (e.g., low specificity and suboptimal kinetics) have been major challenges to successful targeted imaging of specific inflammatory processes. We have synthesized a prototype 99mTc-labeled high- affinity peptide, derived from the carboxy-terminus of a relatively recently identified chemokine, i.e., chemerin, which is internalized by macrophages expressing chemerin receptor 1 (also known as chemokine-like receptor 1 (CMKLR1). The goal of this proposal is to further advance this approach by the synthesis and optimization of novel activatable monomeric and cleavable multimeric tracers for in vivo imaging of chemerin-CMKLR1 axis in inflammation. Our central hypothesis is that the unique design of the activatable chemerin-derived imaging probes allows for accurate in vivo monitoring of inflammation, through taking advantage of: A) protease- mediated activatable mechanism, B) relatively restricted expression of CMKLR1 by immune cells, C) high affinity and subsequent receptor-mediated internalization of the C-terminal peptides, and D) enhanced kinetics of the multimeric peptides. We propose two Specific Aims: SPECIFIC AIM 1: To develop and optimize protease-activatable monomeric and cleavable multimeric chemerin- derived radiotracers. SPECIFIC AIM 2: To validate the accuracy of in vivo imaging using selected optimized tracers in murine models of sterile inflammation. We predict a high degree of species- independency of our tracers, which are derived from the highly conserved carboxy-terminus of chemerin. Thus, this approach may be applied in a variety of animal models and ultimately in humans. Our ultimate goal is to develop an innovative approach for targeted imaging of an important immunoregulatory pathway, i.e., chemerin-CMKLR1 axis, which may provide a venue for precision medicine in a variety of inflammatory diseases.

新型蛋白酶可激活的趋化蛋白衍生示踪剂用于分子成像炎症摘要炎症的分子成像允许早期识别致病性在广泛的疾病过程中，可能导致改善患者的风险分层，监测疾病的进展或对治疗的反应。因此，它是一个主要的驱动力，精准医学的发展，特别是随着新技术的不断发展和应用，免疫调节疗法。然而，目前的分子成像示踪剂的局限性 (e.g.,低特异性和次优动力学）已经是成功靶向的主要挑战特定炎症过程的成像。我们已经合成了一个原型99 mTc标记的高- 亲和肽，衍生自相对新近鉴定的趋化因子的羧基末端，也就是说，chemerin，其被表达chemerin受体1（也称为chemerin receptor 1）的巨噬细胞内化趋化因子样受体1（CMKLR 1）。该提案的目标是进一步推进这一点方法通过合成和优化新的可活化单体和可裂解的用于炎症中趋化蛋白-CMKLR 1轴的体内成像的多聚体示踪剂。我们的中央假设可活化趋化蛋白衍生的成像探针的独特设计允许为了准确地在体内监测炎症，通过利用：A）蛋白酶- 介导的可激活机制，B）免疫细胞相对限制CMKLR 1的表达， C）C-末端肽的高亲和力和随后的受体介导的内化，和 D）多聚体肽的增强的动力学。我们提出两个具体目标：具体目标 1：开发和优化蛋白酶可激活的单体和可切割的多聚体趋化蛋白- 衍生放射性示踪剂。具体目标2：使用选定的优化的示踪剂在无菌炎症的小鼠模型。我们预测会有大量的物种- 我们的示踪剂的独立性，这是来自高度保守的羧基末端， chemerin。因此，这种方法可以应用于各种动物模型，并最终应用于人类我们的最终目标是开发一种创新的方法，重要的免疫调节途径，即，chemerin-CMKLR 1轴，这可能提供了一个场所，用于各种炎症性疾病的精准医疗。