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.

心力衰竭是全球发病率和死亡率的主要原因。心肌病，病理学 基础大多数心力衰竭病例通常是由心肌损伤引起的。这会促进炎症， 成纤维细胞增殖和肌纤维细胞转化，最终是纤维化，这直接有助于 心力衰竭及其并发症的基础的结构变化。结构成像方式，例如 磁共振成像可以在给定点提供心脏结构的快照。但是，他们做到了 不提供有关纤维化过程的任何信息，这是理论干预措施的目标 纤维化的进展和促进。同样，虽然有几个新示踪剂 引入以通过分子成像检测纤维化，这些试剂靶向成熟的胶原蛋白，无法区分 在既定的疾病和正在进行的基质重塑之间，涉及主动纤维发生和 纤维化的分辨率。因此，需要新颖的非侵入性定量工具来表征纤维化， 检测基质周转，选择患者以进行新兴疗法，跟踪热干预的影响， 并提示提示。心脏纤维化主要由I型胶原蛋白和III组成。标志的标志 胶原蛋白结构是三螺旋，是由重复基序形成的3α链的右手螺旋，它们自我自我 组装形成（Pro）胶原纤维。在心室重塑期间，高度有条理的成熟科拉根 纤维被蛋白酶（例如基质金属蛋白酶（MMP））降解为单链的α链，这些蛋白酶 通常不存在于细胞外空间中。基于胶原蛋白转移在心脏中的作用 我们假设重塑并与我们的初步数据结合使用。 可以通过成像单链胶原蛋白来跟踪心室重塑中的纤维化。解决这个问题 假设，作为成像心脏纤维化的一种新型方法，我们建议将新型的放射性示例发展为 通过利用胶原蛋白三重螺旋组装来靶向胶原蛋白更新。这个小说类的胡椒 基于基于的放射性示踪剂设计，包括原型示踪剂 初步研究的有希望的结果。在这里，我们试图进一步将铅示踪剂描述为 需要，并将其评估为微型单光子计算机断层扫描（SPECT）/计算机断层扫描（CT） 替代品和间质性心脏纤维化的鼠模型中的成像，以跟踪纤维化及其分辨率，以及 与MMP靶向成像相比，预测心室重塑。这些研究的结合将 引入和验证一种新型分子成像方法，并具有直接的临床翻译路径 跟踪纤维化及其分辨率，不仅是心肌病，而且还针对其他多种纤维化疾病。