Molecular Imaging of the ChemR23-Chemerin Axis in Acute Lung Injury

急性肺损伤中 ChemR23-Chemerin 轴的分子成像

• 批准号: 10441149
• 负责人: Philip Zachary Mannes
• 金额: $ 5.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441149
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Affinity; Agonist; Alveolar; Asthma; Automobile Driving; Binding; Biochemical; Biological; Biological Markers; Biopsy; Bronchoalveolar Lavage; C-terminal; CMKLR1 gene; Cells; Chemotactic Factors; Chronic; Clinical; Complex; Critical Illness; Dendritic Cells; Detection; Development; Disease; Epithelial Cells; Exhibits; Fright; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gases; Goals; Histologic; Image; Immune; Impairment; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Kinetics; Life; Lipopolysaccharides; Lung; Lung diseases; Measures; Mediating; Methods; Modification; Monitor; Natural Killer Cells; Neutrophil Infiltration; Non-Invasive Cancer Detection; Outcome; Pathogenicity; Patients; Peptide Hydrolases; Peptides; Phase; Phenotype; Plasma; Play; Population; Positron-Emission Tomography; Preparation; Process; Property; Proteolytic Processing; Pulmonary Inflammation; Quality of life; Radiolabeled; Research; Resolution; Risk; Serine Protease; Serum; Site; Specificity; Tail; Tissues; Tracer; Validation; antagonist; base; cell motility; chemokine receptor; clinical practice; clinical prognostic; contrast imaging; design; extracellular; fluorodeoxyglucose; imaging biomarker; imaging probe; immune activation; immunomodulatory therapies; improved; in vivo imaging; indexing; inflammatory milieu; lung injury; macrophage; migration; molecular imaging; mouse model; neutrophil; non-invasive imaging; novel; peptidomimetics; personalized medicine; precision medicine; prognostic; prognostic tool; prototype; radiotracer; receptor; smoke inhalation; uptake

Project Summary Acute lung injury (ALI), clinically known as acute respiratory distress syndrome (ARDS), is a severe and potentially life-threatening condition with different sub-phenotypes leading to distinct clinical outcomes. In particular, patients with non-resolving pulmonary inflammation who survive the acute phase of ARDS are a subpopulation at increased risk for poor outcomes, including long term lung damage and significantly decreased quality of life. Therefore, developing strategies to monitor ongoing lung inflammation based on inflammatory signatures (i.e. specific inflammatory mediators and individual immune cell populations) represents a Precision Medicine approach, especially relevant given the growing development and applications of immunomodulatory therapies. Molecular imaging using positron emission tomography (PET) is emerging as a promising non- invasive approach that can used to visualize inflammatory processes and provide prognostic information. Current PET tracers, primarily 18F-FDG, for lung inflammation suffer from a lack of specificity and poor kinetics. We propose developing PET tracers targeting the receptor/chemokine ChemR23/chemerin, a newly established biomarker for imaging lung inflammation. We have designed two classes of PET tracers, an “active” probe imaging the expression of ChemR23 and an “activatable” probe imaging the inflammatory-protease bioactivation of the ChemR23-chemerin axis. Our central hypothesis is that modification of the “active” tracer into an “activatable” tracer through addition of a cleavable C-terminal tail will enhance the specificity of imaging the ChemR23-chemerin axis by mimicking the local bioactivation and ultimately uptake of chemerin in the inflammatory environment. We propose two specific aims: SPECIFIC AIM 1: To synthesize and biologically characterize active and protease-activatable chemerin-derived radiotracers. SPECIFIC AIM 2: To determine the biological, biochemical, and histological correlates of ChemR23-targeted PET by “active” and “activatable” tracers in a mouse model of ALI. Our ultimate goal is to develop bioactivatable PET tracers for precision medicine imaging of ongoing lung injury and inflammation along the ChemR23-chemerin axis to improve research and clinical prognostic tools.

项目摘要 急性肺损伤(ALI)，临床上称为急性呼吸窘迫综合征(ARDS)，是一种严重和 具有不同亚型的潜在危及生命的疾病导致不同的临床结果。在……里面 特别是，在ARDS急性期幸存下来的未消退的肺部炎症患者是 预后不良风险增加的亚群，包括长期肺损伤，并显著减少 生活质量。因此，开发基于炎症的持续肺部炎症监测策略 签名(即特定的炎症介质和单个免疫细胞群)代表一种精确度 医学方法，特别是考虑到免疫调节剂的日益发展和应用 治疗。使用正电子发射断层扫描(PET)的分子成像是一种很有前途的非 可用于可视化炎症过程并提供预后信息的侵入性方法。当前 肺部炎症的PET示踪剂，主要是18F-FDG，缺乏特异性和较差的动力学。我们 建议开发针对受体/趋化因子ChemR23/趋化蛋白的PET示踪剂 用于肺部炎症成像的生物标志物。我们设计了两类PET示踪剂，一种“主动”探头 显像炎性蛋白水解酶活性的可活化探针及ChemR23的表达 在ChemR23-趋化素轴上。我们的中心假设是将“活性”示踪剂修改为 通过添加可切割的C末端尾巴来激活的示踪剂将增强成像的特异性 通过模拟局部生物激活和最终摄取趋化蛋白来实现趋化素轴 炎性环境。我们提出了两个具体目标：具体目标1：合成和生物 表征活性和可激活的趋化蛋白放射性示踪剂。具体目标2：确定 “活性”和“可激活”与ChemR23靶向PET的生物学、生化和组织学相关性 ALI小鼠模型中的示踪剂。我们的最终目标是开发用于精密医学的可生物激活的PET示踪剂 沿着ChemR23-趋化素轴对持续的肺损伤和炎症进行成像以改进研究和 临床预后工具。