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.

项目概要 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、 具有不同亚表型的潜在危及生命的病症，导致不同的临床结果。在 特别是，在 ARDS 急性期幸存下来的肺部炎症未消退的患者是 不良结果风险增加的亚人群，包括长期肺损伤，并且显着降低 生活质量。因此，制定基于炎症监测持续肺部炎症的策略 特征（即特定炎症介质和个体免疫细胞群）代表精确度 医学方法，特别是考虑到免疫调节的不断发展和应用 疗法。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。当前的 用于肺部炎症的 PET 示踪剂（主要是 18F-FDG）缺乏特异性且动力学较差。我们 建议开发针对受体/趋化因子 ChemR23/chemerin 的 PET 示踪剂，这是一种新建立的 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，一种是“主动”探针 对 ChemR23 的表达进行成像，并用“可激活”探针对炎症蛋白酶生物激活进行成像 ChemR23-凯莫瑞轴。我们的中心假设是将“主动”示踪剂修改为 通过添加可裂解的 C 末端尾部的“可激活”示踪剂将增强成像的特异性 ChemR23-凯莫瑞轴通过模拟局部生物激活并最终摄取凯莫瑞 炎症环境。我们提出两个具体目标： 具体目标 1：合成和生物学 表征活性和蛋白酶可激活的凯莫瑞衍生放射性示踪剂。具体目标 2：确定 通过“活性”和“可激活”确定 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准医疗的生物可激活 PET 示踪剂 沿着 ChemR23-chemerin 轴对正在进行的肺损伤和炎症进行成像，以改进研究和 临床预后工具。