Electrical impedance myography in an animal model

描述（由申请人提供）：总体上产生虚弱和功能障碍的周围神经和肌肉疾病相对常见，包括肌萎缩性侧索硬化症（ALS）、脊髓性肌萎缩症（SMA）、肌营养不良症，甚至老年人的全身性少肌症或肌肉退化。鉴于基础科学的各种发现，大量的新疗法正在进入临床前和临床测试阶段。为了测试这些药物的疗效， 对于早期疾病识别和跟踪疾病进展都是必需的。一种有望作为有效生物标志物的技术是电阻抗肌描记术（EIM）。在这项技术中，通过表面电极向肌肉施加微小电流，并测量所得的表面电压。从这些数据中，获得组织的电阻和电抗，提供关于底层肌肉健康的结构和组成信息。一些人类临床研究正在证明EIM的潜在力量。然而，为了使EIM充分发挥其潜力，仍然需要更好地了解EIM和潜在肌肉病理之间的关系。在过去的4年里，自R 01 -055099基金启动以来，我们在这方面取得了实质性的进展，探索了两种基本大鼠疾病模型的阻抗变化，同时还开发了一套实验和分析工具。在这次更新中，我们计划继续这项工作，将我们的研究扩展到新的和相关的神经肌肉疾病模型，进一步完善EIM的科学和技术。我们广泛的假设是，表面EIM数据的变化反映了肌肉固有的电材料特性，这些特性直接受到肌肉病理的影响。我们计划通过研究四种不同神经肌肉疾病的小鼠模型来测试这一点，并随着疾病的进展比较它们之间和它们内部的数据。除EIM数据外，还将收集行为、电生理和组织学数据。在具体目标1中，我们将研究ALS的SOD 1 G93 A模型中的EIM，作为进行性运动神经元疾病的一个例子。在具体目标2中，我们将在最近开发的FVBn C/C小鼠SMA模型中研究EIM，SMA是一种以原发性和继发性肌肉变性为特征的疾病。在具体目标3中，我们将研究杜氏肌营养不良症MDx小鼠模型中的EIM，其中肌肉中存在显著的结构和组成变化。在具体目标4中，我们将研究老年小鼠模型肌肉减少症的EIM，这种情况是废用和纤维化变化的结合导致肌肉虚弱。作为这项工作的一部分，我们还将应用一些创新，包括精细的测量和分析技术，如收缩和各向异性测量的EIM评估和电流的有限元建模。随着这项研究的成功完成，我们将大大扩展我们的工具，以有效地应用和解释EIM在临床前动物研究和人类临床研究。

DESCRIPTION (provided by applicant): Peripheral nerve and muscle disorders that produce weakness and dysfunction taken as a whole are relatively common and include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), muscular dystrophy, and even the generalized condition of sarcopenia, or muscle deterioration in the elderly. Given a variety of discoveries in basic science, a plethora of new therapies is reaching the stage of pre-clinical and clinical testing. In order to test the efficacy of these drugs, effective, sensitive biomarkers are needed both for early disease identification and for following disease progression. One technique that has the promise of serving as an effective biomarker is electrical impedance myography (EIM). In this technique, a minute electrical current is applied to a muscle via surface electrodes and the resulting surface voltages measured. From these data, the tissue's resistance and reactance are obtained, providing structural and compositional information on the health of the underlying muscle. Several human clinical studies are demonstrating the potential power of EIM. However, in order for EIM to reach its full potential, an improved understanding of the relationship between EIM and underlying muscle pathology is still needed. In the past 4 years since the initiation of grant R01-055099, we have made substantial in-roads in that direction, exploring impedance alterations in two basic rat disease models, while also developing a set of experimental and analytic tools. In this renewal, we plan to continue to this work, expanding our studies into new and relevant models of neuromuscular disease, further refining the science and technology of EIM. Our broad hypothesis is that alterations in surface EIM data reflect the inherent electrical material properties of muscle, and that these properties are directly impacted by muscle pathology. We plan to test this by studying mouse models of four distinct neuromuscular disorders and comparing data across them and within them as the disorders progress. In addition to EIM data, behavioral, electrophysiological, and histological data will be collected. In Specific Aim 1, we will study EIM in the SOD1 G93A model of ALS as an example of a progressive motor neuron disorder. In Specific Aim 2, we will study EIM in the recently developed FVBn C/C mouse model of SMA, a disease characterized by both primary and secondary muscle degeneration. In Specific Aim 3, we will study EIM in the MDx mouse model of Duchenne muscular dystrophy, in which there are marked structural and compositional changes in muscle. And in Specific Aim 4, we will study EIM in the aged mouse model sarcopenia, a condition in which a combination of disuse and fibrotic change renders the muscle weak. As part of this work we will also apply a number of innovations, including refined measuring and analytic techniques, such as EIM assessment of contraction and anisotropic measurement and finite element modeling of electrical current flow. With the successful completion of this research, we will have greatly expanded our tools to effectively apply and interpret EIM in both pre-clinical animal studies and human clinical research.