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），是严重的 潜在的威胁生命的条件具有不同的亚表型，导致不同的临床结果。在 特别是，在ARDS的急性阶段生存的非分辨肺部炎症患者是A 以不良预后风险增加的亚种群，包括长期肺损伤，并显着减少 生活质量。因此，制定策略以根据炎症监测正在进行的肺部感染 签名（即特定的炎症介质和个体免疫细胞种群）代表精度 鉴于免疫调节的发展和应用的不断增长，医学方法尤其相关 疗法。使用正电子发射断层扫描（PET）的分子成像正在成为有望的非 - 可视化炎症过程并提供预后信息的侵入性方法。当前的 宠物示踪剂，主要18F-FDG，用于肺部注射的宠物示踪剂缺乏特异性和动力学差。我们 提案开发针对接收器/趋化因子Chemr23/chemerin的宠物示踪剂，这是一种新建立的 用于成像肺部感染的生物标志物。我们设计了两类宠物示踪剂，一个“活跃”证明了 成像ChemR23的表达和“可激活”的探针成像炎症性蛋白酶生物活化 ChemR23-化合物轴的轴。我们的中心假设是将“主动”示踪剂的修改为 通过添加可裂解的C末端尾部，“可激活”示踪剂将增强成像的特异性 通过模仿局部生物活化并最终吸收Chemerin 炎症环境。我们提出了两个具体目标：特定目的1：合成和生物学上 表征活性和蛋白酶 - 可激活化学蛋白衍生的放射性示例。特定目标2：确定 通过“活跃”和“可启动”靶向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精密医学的可生物活化宠物示踪剂 沿ChemR23-化合物轴的持续肺损伤和炎症的成像，以改善研究和 临床预后工具。