Ethical Considerations in Animal Study Translation

动物研究翻译中的伦理考虑

• 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
• 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

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.

摘要 运动感（动觉）提供了我们在太空中身体动作的内感受性内部读出 这对我们在环境中流畅有效地移动至关重要。尽管动觉 重要性的运动功能和自我参考，我们对这种感觉的理解是困扰着耀眼的知识 差距和不一致。运动感觉在传统上被认为是Ia型的一种特殊功能 肌梭传入然而，这种受体的外围编码特性 而已知的能唤起运动感的感官刺激也引发了关于其主要作用的问题 在动觉上。虽然本体感觉干预提供了许多条件下的功能运动改善 例如中风、帕金森病、局灶性肌张力障碍、周围神经病变和肌肉骨骼损伤， 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， 阻止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，我们有多条证据表明可能存在感觉肌肉受体， 在传统的肌梭和高尔基体腱器官之外， 动觉传感器首先，我们在大鼠中的外周电生理记录显示了一群快速- 传导快速适应传入，其不同于肌梭和高尔基体腱器官传入， 但在与动觉错觉相关的频率带宽中被选择性地激活。二是我们 小鼠骨骼肌中的免疫学分析揭示了大口径钙结合蛋白28 k+的新群体 不与肌梭或高尔基体腱器官受体相关，而是终止于游离的 沿着梭外肌纤维伸展的末端。在一项运动感知研究中， 机器接口截肢者，我们发现振动引起的错觉动觉知觉与肌肉有关， 收缩而不是伸长。这些结果在我们放大的人类中风模型中得到了证实。 动觉感知与主动肌肉收缩有关，这导致改进的到达轨迹。与 根据这些观察，我们假设存在与Ia型不同的候选肌肉感觉传入 选择性地对肌纤维收缩作出反应的传入神经。 本研究将探讨响应特性与物理特性之间的关系， 这些候选动觉受体和传统定义的肌肉感觉受体的特征 使用遗传学、组织学和电生理学方法。此外，我们将研究这些系统 关于收缩特征的功能及其作为主动运动感测刺激的能力。 动觉细胞基础的发现和评估将从根本上改变我们的理解 并将影响高级神经机器接口的设计策略 用于截肢者的假肢装置，以及具有感觉运动缺陷的其他疾病，如中风。

项目成果

Proprioception: A New Era Set in Motion by Emerging Genetic and Bionic Strategies?

• DOI: 10.1146/annurev-physiol-040122-081302
• 发表时间: 2023-02-10
• 期刊: Annual review of physiology
• 影响因子: 18.2