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.

摘要 对损伤的异常免疫应答是创伤后不利的细胞外基质重塑的主要致病驱动因素。 急性肺损伤（ALI）和广泛的纤维化肺疾病（简称炎症-纤维化轴）。 然而，目前还没有建立的方法用于非侵入性评估失调的肺 炎症这种差距沿着的是临床过程的病理生理异质性和变异性 患者已经阻碍了纤维化肺病的精确医学管理。趋化因子样受体-1 （CMKLR 1）是趋化因子受体，在促纤维化单核细胞衍生的巨噬细胞中过表达， 白细胞亚群在肺纤维化的发病机制中起关键作用。我们的核心目标是确定 CMKLR 1靶向PET用于i）肺部炎症定量成像; ii） 疾病进展的风险;和iii）早期监测对抗炎和抗- ALI和纤维化肺损伤实验模型中的纤维化干预。我们还将讨论临床 CMKLR 1靶向PET的相关性及其通过测定表达进行未来临床翻译的潜力 CMKLR 1在COVID-19和几种纤维化肺病患者肺中的表达与健康人相比 对照我们的初步数据显示，一种新型CMKLR 1靶向示踪剂的肺摄取显著增加， （64 Cu-NODAGA-CG 34）在脂多糖诱导的ALI和博来霉素诱导的纤维化的两种小鼠模型中的作用 肺损伤，这主要是由单核细胞衍生的巨噬细胞的积累驱动的。我们的中央 假设i）CMKLR 1作为ALI中单核细胞衍生的巨噬细胞的生物标志物， 纤维化肺疾病;因此其通过64 Cu-NODAGA-CG 34 PET的靶向成像允许ii）预测 进展为持续性炎症和纤维化的风险;和iii）监测早期治疗性免疫抑制剂， 对抗炎和抗纤维化干预的反应。我们提出三个具体目标： 具体目的1：确定A）ALI小鼠模型中表达CMKLR 1的白细胞的免疫特征 和纤维化损伤，以及B）COVID-19和纤维化肺病患者的肺标本。 具体目标2：验证CMKLR 1靶向PET作为不同炎症水平炎症生物标志物的准确性。 在小鼠模型中的ALI和纤维化损伤的分期。 具体目标3：确定CMKLR 1靶向PET在A）疾病诊断和B）早期诊断中的潜力 检测ALI和纤维化肺损伤的鼠模型中的治疗反应。 影响：通过确定CMKLR 1靶向PET在巨噬细胞驱动的炎症成像中的作用， 定义CMKLR 1在各种纤维化肺疾病中的表达，该提议可能导致精确的 允许i）改善风险分层; ii）前瞻性识别高风险患者的药物策略 对抗炎/抗纤维化干预的有利反应的可能性（因此，避免其他 副作用和成本）;及iii）基于早期监测反应的个性化治疗调整。