Biophysical Basis of Muscle Functional MRI

描述（由申请人提供）：这是R01奖项“肌肉功能MRI的生物物理基础”的竞争性更新申请。在上一周期中，我们进一步了解了骨骼肌MRI对比的生理基础，特别是血氧水平依赖性（BOLD）效应，并开发了用于定量表征肌肉结构的弥散张量MRI （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，然后将它们用于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肌营养不良蛋白的缺失或功能失调。由此产生的表型包括炎症、肌肉纤维坏死伴脂肪替代和纤维化、灌注缺陷和最大应激能力降低。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纤维结构，损害了肌纤维几何形状、应力和应变发展以及灌注之间的正常关系。因此，我们这项应用的总体目标是推进表征骨骼肌结构和功能的MRI技术，以阐明肌营养不良症中骨骼肌结构异常与机械和生理功能受损之间联系的新方面。目的1是量化脂肪浸润肌肉的肌肉结构模式，以及在等长收缩过程中结构与应变发展之间的正常关系。这些研究将建立在之前拨款周期中DT-MRI纤维跟踪的进展基础上，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血流量、体积和氧合变化，并确定纤维曲率对灌注的影响。该目标将利用我们在上一个资助期间建立的骨骼肌BOLD对比的改进理解，并将这些方法与灌注和血容量测量相结合，以全面表征运动肌肉的氧气输送和使用。目的3是量化健康和营养不良肌肉中骨骼肌结构、肌肉劳损发展、血流和氧化代谢之间的关系。这些研究将建立在先前资助期间完成的工作的基础上，为表征健康和疾病的骨骼肌提供新的工具，并为骨骼肌中功能性肌营养不良蛋白丧失的病理过程提供新的见解。

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.