Biophysical Basis of Muscle Functional MRI

描述(由申请人提供)：这是一份R01奖的竞争性续展申请书，标题为“肌肉功能磁共振的生物物理基础”。在上一个周期中，我们对骨骼肌MRI对比剂的生理基础，特别是血氧水平依赖(BOLD)效应有了更深入的了解，并开发了用于定量表征肌肉结构的扩散-张量成像(DT-MRI)纤维跟踪方法。在拟议的研究中，我们将进一步推进这些技术，然后将其应用于Becker和Duchenne肌营养不良症。这些是严重的神经肌肉疾病，其特征是细胞骨架蛋白Dstrophin缺失或功能失调。由此产生的表型包括炎症，肌肉纤维坏死，脂肪替代和纤维化，灌注不足，以及最大应力产生能力降低。在这个应用中，我们提出了一个新的假设，即脂肪替代改变了正常的肌肉纤维结构，损害了肌肉纤维几何形状、应力和应变发展以及灌流之间的正常关系。因此，我们这项应用的总体目标是发展MRI技术来表征骨骼肌的结构和功能，以阐明骨骼肌结构异常与肌营养不良症的机械和生理性能受损之间的联系的新方面。目标1是量化脂肪渗透肌肉中的肌肉结构模式，以及在等长收缩过程中肌肉结构和应变发展之间的正常关系。这些研究将建立在DT-MRI纤维追踪在前一个资助周期中取得的进展的基础上，并提供对正常肌肉结构-功能关系的新理解。目的2是开发和实施改进的MRI方法来量化运动过程中肌肉的血流量、体积和氧合变化，并确定纤维曲率对血流灌注的影响。这一目标将利用我们在上一次资助期间建立的对骨骼肌大胆对比的更好的理解，并将这些方法与灌注和血容量测量相结合，以通过锻炼肌肉来全面表征氧气的输送和使用。目的3是量化健康和营养不良肌肉的骨骼肌结构、肌肉应变发育、血流和氧化代谢之间的关系。这些研究将建立在前一资助期间完成的工作的基础上，为确定骨骼肌在健康和疾病中的特征提供新的工具，并为骨骼肌中伴随功能性肌营养不良蛋白丧失的病理过程提供新的见解。 公共卫生意义：Becker肌营养不良症是一种以肌肉萎缩为特征的严重神经肌肉疾病。然而，与这种浪费相关的功能缺陷还没有完全被理解。在这一应用中，我们将开发新的磁共振成像技术来研究这些缺陷。

DESCRIPTION (provided by applicant): This is an application for competitive renewal of an R01 award entitled "Biophysical Basis of Muscle Functional MRI." In the previous cycle, we developed an improved understanding of the physiological basis of MRI contrast in skeletal muscle, especially blood oxygenation-level dependent (BOLD) effects, and developed diffusion-tensor MRI (DT-MRI) fiber tracking methods for quantitative characterization of muscle structure. In the proposed studies, we will advance these techniques further and then bring them to bear on Becker and Duchenne muscular dystrophy. These are severe neuromuscular disorders characterized by a missing or dysfunctional form of the cytoskeletal protein dystrophin. The resulting phenotype includes inflammation, muscle fiber necrosis with fat replacement and fibrosis, perfusion deficits, and reduced maximum stress- generating capability. In this application, we propose the novel hypothesis that fat replacement alters the normal muscle fiber architecture, impairing the normal relationships among muscle fiber geometry, stress and strain development, and perfusion. Therefore, our overall objective for this application is to advance MRI techniques for characterizing skeletal muscle structure and function, in order to elucidate novel aspects of the linkage between the skeletal muscle structural abnormalities and impaired mechanical and physiological performance in the dystrophinopathies. Aim 1 is to quantify muscle architecture patterns in fat-infiltrated muscle and the normal relationship between architecture and strain development during isometric contractions. These studies will build on the advancements made in DT-MRI fiber tracking in the previous grant cycle and provide new understanding of normal muscle structure-function relationships. Aim 2 is to develop and implement improved MRI methods for quantifying muscle blood flow, volume, and oxygenation changes during exercise and determine the effect of fiber curvature on perfusion. This aim will capitalize on the improved understanding of BOLD contrast in skeletal muscle that we built during the last funding period and integrate these methods with perfusion and blood volume measurements for a comprehensive characterization of oxygen delivery and use by exercising muscle. Aim 3 is to quantify the relationships among skeletal muscle architecture, muscle strain development, blood flow, and oxidative metabolism in healthy and dystrophic muscle. These studies will build on the work accomplished during the previous funding period, advance new tools for characterizing skeletal muscle in health and disease, and provide new insight into the pathological processes accompanying the loss of functional dystrophin in skeletal muscle. PUBLIC HEALTH RELEVANCE: Becker muscular dystrophy is a severe neuromuscular disorder characterized by muscle wasting. However, the functional deficits associated with this wasting are not completely understood. In this application, we will develop new magnetic resonance imaging techniques for studying these deficits.