Molecular Imaging of Collagen Turnover in Cardiomyopathy

心肌病中胶原蛋白周转的分子成像

• 批准号: 10645228
• 负责人: MEHRAN M SADEGHI
• 金额: $ 79.57万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645228
• 关键词: Address; Affinity; Aorta; Aortic Valve Stenosis; Binding; Biological; Cardiac; Cardiomyopathies; Characteristics; Cicatrix; Classification; Collagen; Collagen Fiber; Collagen Type I; Data; Deposition; Development; Diagnostic; Diffuse; Disease; Drug Kinetics; Extracellular Space; Fibroblasts; Fibrosis; Functional disorder; Glycine; Heart; Heart Hypertrophy; Heart failure; Histology; Hydroxyproline; Hypertension; Hypertrophic Cardiomyopathy; Image; In Vitro; Infarction; Inflammation; Injury; Integrins; Lead; Left Ventricular Remodeling; Magnetic Resonance Imaging; Matrix Metalloproteinases; Modeling; Molecular Structure; Morbidity - disease rate; Myocardial Infarction; Myocardium; Myofibroblast; Pathology; Patient Selection; Peptide Hydrolases; Peptides; Performance; Photons; Positron-Emission Tomography; Process; Proliferating; Proline; Resolution; Role; Secondary to; Specificity; Structure; Therapeutic Effect; Therapeutic Intervention; Tissues; Tracer; Ventricular; Ventricular Remodeling; X-Ray Computed Tomography; aorta constriction; clinical translation; coronary fibrosis; design; fibrogenesis; heart imaging; imaging agent; imaging approach; imaging modality; improved; in vivo; interstitial; lead optimization; microSPECT; molecular imaging; mortality; mouse model; myocardial injury; novel; novel strategies; pressure; prevent; prognostic; prognostication; prototype; radiotracer; self assembly; single photon emission computed tomography; structural imaging; targeted agent; targeted imaging; targeted treatment; tool; triple helix

Heart failure is a major cause of morbidity and mortality worldwide. Cardiomyopathy, the pathology that underlies most cases of heart failure is often triggered by myocardial injury. This promotes inflammation, fibroblast proliferation and myofibroblast transformation, and ultimately fibrosis, which directly contributes to structural changes that underlie heart failure and its complications. Structural imaging modalities such as magnetic resonance imaging can provide a snapshot of cardiac structure at a given point. However, they do not provide any information on the fibrotic process, which is the target of therapeutic interventions to prevent the progression and promote the regression of fibrosis. Similarly, while several new tracers have been introduced to detect fibrosis by molecular imaging, these agents target mature collagen and cannot distinguish between established disease and ongoing matrix remodeling which accompanies active fibrogenesis and resolution of fibrosis. Therefore, novel non-invasive quantitative tools are needed to characterize fibrosis, detect matrix turnover, select the patients for emerging therapies, track the effect of therapeutic interventions, and improve prognostication. Cardiac fibrosis consists mainly of collagen types I and III. The hallmark of collagen structure is triple helix, a right-handed helix of 3 α-chains formed by repetitive motifs, which self- assemble to form (pro)collagen fibers. During ventricular remodeling, the highly organized mature collagen fibers are degraded by proteases such as matrix metalloproteinases (MMPs) into single stranded α-chains that are not normally present in the extracellular space. Based on the role of collagen turnover in cardiac remodeling and in conjunction with our preliminary data, we hypothesize that the development and regression of fibrosis in ventricular remodeling can be tracked by imaging single stranded collagen. To address this hypothesis, and as a novel approach to imaging cardiac fibrosis, we propose to develop novel radiotracers to target collagen turnover by taking advantage of collagen triple helix self-assembly. This novel class of peptide- based radiotracers is designed with a modular structure and includes a prototype tracer which has yielded promising results in preliminary studies. Here, we seek to further characterize and optimize the lead tracer as needed, and evaluate it for micro single photon computed tomography (SPECT)/computed tomography (CT) imaging in murine models of replacement and interstitial cardiac fibrosis to track fibrosis and its resolution, and to predict ventricular remodeling in comparison with MMP-targeted imaging. Combined these studies will introduce and validate a novel molecular imaging approach with a straightforward path to clinical translation to track fibrosis and its resolution, for not only cardiomyopathy, but also a wide range of other fibrotic disorders.

心力衰竭是世界范围内发病率和死亡率的主要原因。心肌病是一种 大多数心力衰竭的基础往往是由心肌损伤引起的。这会促进炎症， 成纤维细胞增殖和肌成纤维细胞转化，并最终纤维化，这直接有助于 导致心力衰竭及其并发症的结构变化。结构成像模式，如 磁共振成像可以提供给定点处心脏结构的快照。但他们 不提供任何关于纤维化过程的信息，这是预防纤维化的治疗干预的目标。 并促进纤维化的消退。同样，虽然一些新的示踪剂已经被 引入通过分子成像检测纤维化，这些药物靶向成熟胶原蛋白， 已确立的疾病和正在进行的基质重塑之间的关系， 纤维化消退。因此，需要新的非侵入性定量工具来表征纤维化， 检测基质转换，选择患者进行新兴疗法，跟踪治疗干预的效果， 并改善粘附性。心脏纤维化主要由I型和III型胶原组成。的标志 胶原蛋白结构是三股螺旋，即由重复基序形成的3条α链的右旋螺旋， 组装以形成（原）胶原纤维。在心室重塑过程中，高度组织化的成熟胶原 纤维被蛋白酶如基质金属蛋白酶（MMP）降解成单链α链， 通常不存在于细胞外空间。基于胶原更新在心脏中的作用， 重塑，并结合我们的初步数据，我们假设，发展和回归， 可以通过对单链胶原进行成像来追踪心室重塑中的纤维化。为了解决这个 假设，并作为一种新的方法来成像心脏纤维化，我们建议开发新的放射性示踪剂， 利用胶原三螺旋自组装靶向胶原周转。这种新型的肽- 的放射性示踪剂设计有模块化结构，并包括原型示踪剂， 在初步研究中取得了可喜的成果。在这里，我们寻求进一步表征和优化铅示踪剂， 需要，并评价其用于微型单光子计算机断层扫描（SPECT）/计算机断层扫描（CT） 在替代和间质性心脏纤维化的鼠模型中进行成像以跟踪纤维化及其消退，以及 与MMP靶向成像相比预测心室重构。结合这些研究， 介绍并验证一种新的分子成像方法，该方法具有直接的临床转化途径， 跟踪纤维化及其解决方案，不仅适用于心肌病，还适用于各种其他纤维化疾病。