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.

心力衰竭是全世界发病和死亡的主要原因。心肌病，病理学 大多数心力衰竭病例的根本原因往往是由心肌损伤引发。这会促进炎症， 成纤维细胞增殖和肌成纤维细胞转化，最终导致纤维化，这直接导致 心力衰竭及其并发症的结构变化。结构成像模式，例如 磁共振成像可以提供给定点的心脏结构快照。然而，他们确实 不提供有关纤维化过程的任何信息，纤维化过程是预防治疗干预的目标 的进展并促进纤维化的消退。同样，虽然一些新的示踪剂已被 这些药物是通过分子成像检测纤维化而引入的，它们以成熟的胶原蛋白为目标，无法区分 既定疾病与伴随活性纤维发生的持续基质重塑之间 纤维化的解决。因此，需要新的非侵入性定量工具来表征纤维化， 检测基质周转，选择新疗法的患者，跟踪治疗干预的效果， 并改善预测。心脏纤维化主要由 I 型和 III 型胶原蛋白组成。其标志是 胶原蛋白结构为三螺旋，即由重复基序形成的 3 条 α 链的右旋螺旋， 组装形成（原）胶原纤维。在心室重塑过程中，高度组织化的成熟胶原蛋白 纤维被基质金属蛋白酶 (MMP) 等蛋白酶降解成单链 α 链， 通常不存在于细胞外空间。基于胶原蛋白更新在心脏中的作用 重构并结合我们的初步数据，我们假设发展和回归 心室重塑中的纤维化可以通过单链胶原成像来追踪。为了解决这个问题 假设，并且作为心脏纤维化成像的新方法，我们建议开发新型放射性示踪剂 利用胶原蛋白三螺旋自组装来靶向胶原蛋白周转。这类新型肽- 基于放射性示踪剂的设计采用模块化结构，并包括一个原型示踪剂，该原型已产生 初步研究取得了有希望的结果。在这里，我们寻求进一步表征和优化先导示踪剂： 需要，并对其进行微单光子计算机断层扫描（SPECT）/计算机断层扫描（CT）评估 在替代性和间质性心脏纤维化的小鼠模型中进行成像以追踪纤维化及其消退，以及 与 MMP 靶向成像相比预测心室重塑。综合这些研究将 介绍并验证一种新颖的分子成像方法，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，还适用于多种其他纤维化疾病。