Electrical impedance myography in an animal model

描述(申请人提供)：周围神经和肌肉疾病，导致虚弱和整体功能障碍是相对常见的，包括肌萎缩侧索硬化症(ALS)，脊髓性肌萎缩症(SMA)，肌营养不良，甚至全身情况下的骨骼肌减少，或肌肉退化的老年人。鉴于在基础科学方面的各种发现，过多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，有效的、敏感的生物标志物 对于早期疾病识别和跟踪疾病进展都是必要的。一种有望作为有效生物标志物的技术是电阻抗肌图(EIM)。在这项技术中，通过表面电极向肌肉施加微小的电流，并测量产生的表面电压。从这些数据中，可以获得组织的阻力和电抗，从而提供有关潜在肌肉健康状况的结构和成分信息。几项人类临床研究正在证明EIM的潜在力量。然而，为了充分发挥EIM的潜力，仍然需要更好地理解EIM与潜在的肌肉病理之间的关系。在R01-055099资助启动以来的过去4年里，我们在这个方向上取得了实质性的进展，探索了两个基本的大鼠疾病模型中的阻抗变化，同时也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神经肌肉疾病的新的和相关的模型，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属性，并且这些属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。除了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，我们将研究肌萎缩侧索硬化症的SOD1G93A模型中的EIM作为进行性运动神经元障碍的例子。在具体目标2中，我们将在最近发展的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退化为特征的疾病。在具体目标3中，我们将在Duchenne肌营养不良的MDX小鼠模型中研究EIM，在该模型中，肌肉有显著的结构和成分变化。在特定的目标4中，我们将研究EIM在老年小鼠模型石棺减少中的作用，在这种情况下，停用和纤维化改变的组合使肌肉变得虚弱。作为这项工作的一部分，我们还将应用一些创新技术，包括改进的测量和分析技术，如收缩和各向异性测量的EIM评估以及电流流动的有限元建模。随着这项研究的成功完成，我们将极大地扩展我们的工具，以便在临床前动物研究和人类临床研究中有效地应用和解释EIM。

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.