CMKLR1-Targeted Molecular Imaging of Inflammation as a Precision Medicine Tool in Acute Lung Injury and Fibrotic Lung Diseases

CMKLR1 靶向炎症分子成像作为急性肺损伤和纤维化肺疾病的精准医学工具

• 批准号: 10733483
• 负责人: Sina Tavakoli
• 金额: $ 64.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733483
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Adverse effects; Anti-Inflammatory Agents; Biological; Biological Assay; Biological Markers; Bleomycin; CMKLR1 gene; COVID-19; COVID-19 patient; Categories; Clinical; Data; Development; Dexamethasone; Diesel Exhaust; Disease; Disease Outcome; Disease Progression; Disease stratification; Early Diagnosis; Experimental Models; Extracellular Matrix; Fibrosis; Flow Cytometry; Future; Goals; Heterogeneity; Histologic; Histology; Image; Immune response; Inflammation; Inflammatory; Injury; Interstitial Lung Diseases; Intervention; Label; Leukocytes; Ligands; Lipopolysaccharides; Lung; Lung diseases; Macrophage; Mediating; Molecular Target; Monitor; Occupational; Organ; Pathogenesis; Pathogenicity; Pathologic Processes; Patients; Pirfenidone; Plasma; Play; Positron-Emission Tomography; Process; Pulmonary Fibrosis; Pulmonary Inflammation; Pulmonary function tests; Role; Sarcoidosis; Severities; Severity of illness; Specimen; Techniques; Tissues; Tracer; Validation; Viral Pneumonia; X-Ray Computed Tomography; chemokine receptor; cigarette smoke-induced; clinical translation; clinically relevant; cost; diagnostic strategy; disease prognosis; disorder risk; fibrotic interstitial lung disease; fibrotic lung; fibrotic lung disease; improved; inflammatory lung disease; lung injury; molecular imaging; monocyte; mortality risk; mouse model; novel; novel marker; overexpression; particle; patient stratification; peptidomimetics; personalized management; personalized medicine; precision medicine; prognostication; progression risk; prospective; quantitative imaging; radiotracer; recruit; response; response to injury; risk prediction; risk stratification; spatiotemporal; targeted imaging; tool; treatment response; uptake

ABSTRACT Aberrant immune response to injury is a major pathogenic driver of adverse extracellular matrix remodeling after acute lung injury (ALI) and a wide range of fibrotic lung diseases (referred to inflammation-fibrosis axis). However, there is currently no established approach for noninvasive assessment of dysregulated lung inflammation. This gap along with the pathophysiological heterogeneity and variability of the clinical course of patients has hampered precision medicine management of fibrotic lung diseases. Chemokine-like receptor-1 (CMKLR1) is chemokine receptor which is overexpressed in profibrotic monocyte-derived macrophages, a leukocyte subset with crucial roles in the pathogenesis of lung fibrosis. Our central goal is to determine the potential of CMKLR1-targeted PET for i) quantitative imaging of lung inflammation; ii) prognostication of the risk of disease progression; and iii) early monitoring of the response to anti-inflammatory and anti- fibrotic interventions in experimental models of ALI and fibrotic lung injury. We will also address the clinical relevance of CMKLR1-targeted PET and its potential for future clinical translation by determining the expression of CMKLR1 in the lungs of patients with COVID-19 and several categories of fibrotic lung diseases vs. healthy controls. Our preliminary data revealed a significant increase in lung uptake of a novel CMKLR1-targeted tracer (64Cu-NODAGA-CG34) in two murine models of lipopolysaccharide-induced ALI and bleomycin-induced fibrotic lung injury, which was primarily driven by the accumulation of monocyte-derived macrophages. Our central hypothesis is that i) CMKLR1 serves as a biomarker of monocyte-derived macrophages in ALI and fibrotic lung diseases; hence its targeted imaging by 64Cu-NODAGA-CG34 PET allows for ii) predicting the risk of progression into sustained inflammation and fibrosis; and iii) monitoring the early therapeutic response to anti-inflammatory and anti-fibrotic interventions. We propose three Specific Aims: Specific Aim 1: To determine the immunoprofile of CMKLR1-expressing leukocytes in A) murine models of ALI and fibrotic injury, and B) lung specimens of patients with COVID-19 and fibrotic lung diseases. Specific Aim 2: To validate the accuracy of CMKLR1-targeted PET as a biomarker of inflammation at different stages of ALI and fibrotic injury in murine models. Specific Aim 3: To determine the potential of CMKLR1-targeted PET in A) disease prognostication; and B) early detection of the therapeutic response in murine models of ALI and fibrotic lung injury. Impact: By determining the role of CMKLR1-targeted PET for imaging macrophage-driven inflammation and defining the expression of CMKLR1 across various fibrotic lung diseases, this proposal may lead to a precision medicine strategy that allows for i) improved risk stratification; ii) prospective identification of patients with a high likelihood of favorable response to anti-inflammatory/anti-fibrotic interventions (hence, sparing the others from adverse effects and costs); & iii) personalized treatment adjustment based on early monitoring of the response.

抽象的 对损伤的异常免疫反应是不良细胞外基质重塑后的主要致病驱动力 急性肺损伤（ALI）和多种纤维化肺部疾病（称为炎症纤维化轴）。 但是，目前尚无对肺失调无创评估的既定方法 炎。该差距以及临床过程的病理生理异质性和可变性 患者阻碍了纤维化肺部疾病的精确药物管理。趋化因子样受体1 （CMKLR1）是趋化因子受体，在纤维细胞衍生的巨噬细胞中过表达，A 白细胞子集，在肺纤维化的发病机理中具有关键作用。我们的核心目标是确定 CMKLR1靶向PET的潜力i）肺部炎症的定量成像； ii）预后 疾病进展的风险； iii）早期监测对抗炎和抗炎的反应 ALI和纤维化肺损伤实验模型中的纤维化干预措施。我们还将解决临床 CMKLR1靶向PET的相关性及其在未来临床翻译中的潜力通过确定表达 CMKLR1的肺肺肺部患者与19例患者的肺和几类纤维化的肺部疾病与健康 控件。我们的初步数据显示，新型CMKLR1靶向示踪剂的肺吸收显着增加 （64cu-nodaga-cg34）在两个脂多糖诱导的ALI和博来霉素诱导的纤维化的鼠模型中 肺损伤主要由单核细胞衍生的巨噬细胞的积累驱动。我们的中心 假设是i）cmklr1是ALI和 纤维化肺部疾病；因此，其目标成像由64cu-nodaga-cg34 PET允许ii）预测 发展为持续炎症和纤维化的风险； iii）监测早期治疗 对抗炎和抗纤维化干预措施的反应。我们提出了三个具体目标： 特定目的1：确定在A）ALI的鼠模型中表达CMKLR1的白细胞的免疫剂 和纤维化损伤，以及b）肺部1900和纤维化肺部疾病的肺标本。 特定目的2：验证CMKLR1靶向PET的准确性是在不同的炎症的生物标志物 鼠模型中ALI和纤维化损伤的阶段。 特定目的3：确定cmklr1靶向宠物在A）疾病预后的潜力； b）早 在ALI和纤维化肺损伤的鼠模型中检测治疗反应。 影响：通过确定CMKLR1靶向PET在成像巨噬细胞驱动的炎症和 定义CMKLR1在各种纤维化肺部疾病中的表达，该建议可能会导致精度 允许i）改善风险分层的医学策略； ii）前瞻性鉴定高的患者 对抗炎/抗纤维化干预措施有利反应的可能性（因此，其他 不利影响和成本）； ＆iii）基于对响应的早期监测的个性化治疗调整。