Ethical Considerations in Animal Study Translation

动物研究翻译中的伦理考虑

基本信息

批准号：
10790093
负责人：
Paul D. Marasco
金额：
$ 16万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-06 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10790093
关键词：
Address Amputees Animal Experimentation Animal Model Animals Attention Basic Science Bioethics Biomedical Research Brain Caliber Characteristics Clinical Clinical Research Code Conflict of Interest Consensus Consent Consent Forms Data Discipline Disclosure Disease Electrophysiology (science)Enrollment Environment Esthesia Ethics Evaluation Exhibits Focal Dystonias Foundations Frequencies Future Genetic Goals Golgi Tendon Organs Histologic Human Immunologics Individual Informed Consent Intervention Intervention Studies Kinesthesis Kinesthetic Illusions Knowledge Learning Link Liquid substance Methodology Modeling Motor Movement Mus Muscle Muscle Contraction Muscle Fibers Muscle Spindles Nature Outcome Parkinson Disease Participant Perception Peripheral Peripheral Nervous System Diseases Phase Population Process Property Prosthesis Protocols documentation Questionnaires Rattus Reflex action Reproducibility Research Research Personnel Risk Role Science Sensory Sensory Receptors Skeletal Muscle Stimulus Stroke System Translating Translational Research Translations Uncertain Risk Uncertainty Work clinical care design exposed human population improved innovation motor control motor deficit musculoskeletal injury neural neural circuit pre-clinical pre-clinical research preclinical study preservation prevent prospective public trust receptor research in practice response sensor sensory stimulus statistics stroke model success translational study vibration

项目摘要

Abstract The sense of movement (kinesthesia) provides an interoceptive internal readout of our physical actions in space and is essential for our ability to move fluidly and effectively through our environment. Despite kinesthesia’s importance in motor function and self-reference, our understanding of this sense is plagued by glaring knowledge gaps and inconsistencies. Movement sensations are traditionally believed to be a specialized function of type Ia muscle spindle afferents. Yet, the apparent disconnect between the peripheral coding properties of this receptor and the sensory stimuli known to evoke a sense of movement have raised questions regarding their primary role in kinesthesia. Although proprioceptive interventions provide functional motor improvements for many conditions such as stroke, Parkinson’s disease, focal dystonia, peripheral neuropathies, and musculoskeletal injuries, the lack of a clear scientific foundation for kinesthesia impacts our understanding of sensory-motor deficits and prevents important breakthroughs from translating into clinical successes and targeted intervention strategies. From our recent work we have multiple lines of evidence that suggest there may be sensory muscle receptors, outside of the traditional muscle spindles and Golgi tendon organs that exhibit features consistent with a kinesthetic sensor. First, our peripheral electrophysiological recordings in rat demonstrate a population of fast- conducting rapidly-adapting afferents, that are distinct from muscle spindle and Golgi tendon organ afferents, yet are selectively activated in the frequency bandwidth associated with kinesthetic illusions. Second, our immunological analyses in mouse skeletal muscle reveal a new population of large caliber Calbindin28k+ afferents that do not associate with muscle spindle or Golgi tendon organ receptors but instead terminate in free endings that spread out alongside extrafusal muscle fibers. In a movement-perception study with human neural- machine interface amputees, we found that vibration-induce illusory kinesthetic percepts were linked to muscle contraction not elongation. These results were corroborated in a human stroke model where we amplified kinesthetic perception linked to active muscle contraction which resulted in improved reaching trajectories. With these observations we hypothesize that there are candidate muscle sensory afferents, distinct from type Ia afferents, which selectively respond to muscle fiber contraction. The studies in this proposal will explore the relationships between the response properties and physical characteristics of these candidate kinesthetic receptors and the traditionally defined muscle sensory receptors using genetic, histological, and electrophysiological approaches. Additionally, we will examine this systems functionality with respect to contractile features and its ability to serve as a stimulus for active movement sensing. The discovery and evaluation of the cellular basis of kinesthesia will fundamentally transform our understanding of sensory-motor control and, by extension, will impact design strategies for advanced neural-machine interface prosthetic devices for amputees, as well as other disorders with sensory-motor deficiencies such as stroke.

抽象的运动意识（运动感觉）提供了对我们在太空中的身体行为的内部识别的内部读数对于我们在环境中流畅有效地移动的能力至关重要。尽管有动力学在运动功能和自我参考中的重要性，我们对这种意义的理解受到巨大的知识的困扰差距和不一致。传统上认为运动感觉是IA型的专业功能肌肉主轴传入。但是，该接收器的外围编码属性之间的明显断开连接并且感官刺激唤起运动感已引发了有关其主要作用的问题在动力学中例如中风，帕金森氏病，局灶性肌张力障碍，周围神经病和肌肉骨骼损伤，缺乏明确的科学基础，影响了我们对感觉运动缺陷和的理解防止重要的突破转化为临床成功和有针对性的干预策略。从我们最近的工作中，我们有多种证据表明可能有感觉肌肉接收器，在传统的肌肉纺锤体和高尔基肌腱器官之外，暴露了与运动觉传感器。首先，我们在大鼠中的周围电生理记录表明进行快速适应的传入，与肌肉纺锤体和高尔基肌腱传入不同，然而，在与动力学幻觉相关的频率带宽中有选择地激活。第二，我们的小鼠骨骼肌中的免疫学分析显示，新的含量大的口径Calbindin28k+ 与肌肉纺锤体或高尔基肌腱器官受体不关联但终止自由的传入结束与外部肌肉纤维一起散布的结尾。在人类神经的运动感知研究中机器界面截距，我们发现振动引起的虚幻运动感知与肌肉有关收缩而不是伸长。这些结果在人类中风模型中得到了证实动力学感知与活跃的肌肉收缩有关，从而改善了到达轨迹。和这些观察结果我们假设存在候选肌肉感觉传入，与IA型不同传入，有选择地对肌肉纤维收缩做出反应。该提案中的研究将探讨响应属性与物理之间的关系这些候选动力学受体和传统定义的肌肉感觉受体的特征使用遗传，组织学和电生理方法。此外，我们将检查此系统关于收缩特征的功能及其作为主动运动感测的刺激的能力。动力学细胞基础的发现和评估将从根本上改变我们的理解感觉运动控制，并扩展会影响高级神经机界面的设计策略截肢者的假肢设备以及其他具有感官运动缺陷（例如中风）的疾病。