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: 10228139
• 负责人: Philip Zachary Mannes
• 金额: $ 5.1万
• 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/10228139
• 关键词: Acute; Acute Lung Injury; Adult 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; Cleaved cell; 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 Inflammation; 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; base; cell motility; chemokine receptor; clinical practice; 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），是一种严重的， 可能危及生命的疾病，不同的亚表型导致不同的临床结局。在 特别是，在ARDS急性期存活下来的肺部炎症未消退的患者是一种 不良结局风险增加的亚群，包括长期肺损伤， 生活质量因此，开发基于炎症反应监测进行中的肺部炎症的策略， 特征（即特异性炎症介质和个体免疫细胞群）代表精密度 医学的方法，特别是相关的日益发展和应用的免疫调节 治疗使用正电子发射断层扫描（PET）的分子成像正在成为一种有前途的非成像技术。 侵入性方法可用于可视化炎症过程并提供预后信息。电流 用于肺部炎症的PET示踪剂，主要是18F-FDG，缺乏特异性和动力学差。我们 我建议开发针对受体/趋化因子ChemR 23/chemerin的PET示踪剂，这是一种新建立的 用于成像肺部炎症的生物标志物。我们设计了两类PET示踪剂，一种是“主动”探针， 成像ChemR 23的表达和成像炎性蛋白酶生物活化的“可活化”探针 ChemR 23-chemerin轴。我们的中心假设是，将“活性”示踪剂修饰成 通过添加可裂解的C末端尾的“可活化的”示踪剂将增强对肿瘤细胞成像的特异性。 ChemR 23-chemerin轴通过模拟局部生物活化和最终摄取chemerin在 炎症环境。我们提出了两个具体目标：具体目标1：合成和生物 表征活性和蛋白酶可活化的趋化蛋白衍生的放射性示踪剂。具体目标2：确定 通过“活性”和“可活化”分析ChemR 23靶向PET的生物学、生物化学和组织学相关性 在ALI小鼠模型中的示踪剂。我们的最终目标是为精准医学开发可生物活化的PET示踪剂 沿着ChemR 23-chemerin轴对正在进行的肺损伤和炎症进行成像，以改善研究， 临床预后工具。