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.

抽象的运动感（动觉）提供了我们在空间中的身体动作的内感受内部读数尽管有动觉，但它对于我们在环境中流畅有效地移动的能力至关重要。运动功能和自我参照的重要性，我们对这种感觉的理解受到明显知识的困扰传统上认为运动感觉是 Ia 型的特殊功能。然而，该受体的外周编码特性之间存在明显的脱节。已知能唤起运动感的感官刺激引发了对其主要作用的质疑尽管本体感觉干预可以改善许多情况下的功能性运动。例如中风、帕金森病、局灶性肌张力障碍、周围神经病和肌肉骨骼损伤，缺乏明确的动觉科学基础影响了我们对感觉运动缺陷的理解阻碍重要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存在感觉肌肉受体，在传统的肌梭和高尔基腱器官之外，它们表现出与首先，我们对大鼠的外周电生理记录表明，有一群快速运动的人。传导快速适应的传入，与肌梭和高尔基腱器官传入不同，然而，它们在与动觉错觉相关的频率带宽中被选择性地激活。小鼠骨骼肌免疫学分析揭示了大口径 Calbindin28k+ 的新群体传入神经不与肌梭或高尔基腱器官受体相关，而是以自由终止在一项针对人类神经的运动感知研究中，末端沿着梭外肌纤维展开。对于机器界面截肢者，我们发现振动引起的虚幻动觉知觉与肌肉有关这些结果在我们放大的人类中风模型中得到了证实。动觉知觉与主动肌肉收缩相关，从而改善了到达轨迹。我们观察到存在与 Ia 型不同的候选肌肉感觉传入传入神经，选择性地响应肌纤维收缩。本提案中的研究将探讨响应特性与物理之间的关系这些候选动觉受体和传统定义的肌肉感觉受体的特征此外，我们将使用遗传、组织学和电生理学方法来检查该系统。收缩特征的功能及其作为主动运动传感刺激的能力。动觉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，进而影响先进神经机器接口的设计策略截肢者的假肢装置，以及其他伴有感觉运动缺陷的疾病（如中风）。