Effect of Injury Severity and Location on Spasms Post SCI

损伤严重程度和部位对 SCI 后痉挛的影响

• 批准号: 9320931
• 负责人: VICKI M TYSSELING
• 金额: $ 13.07万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-07 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320931
• 关键词: Academia; Affect; Animals; Area; Attenuated; Award; Basic Science; Behavior; Behavioral; Bone Density; Chairperson; Chicago; Chronic; Clinic; Clinical; Clinical Treatment; Dedications; Development; Disinhibition; Doctor of Philosophy; Dorsal; Educational process of instructing; Electrophysiology (science); Equipment; Fellowship; Goals; Growth Factor; Growth and Development function; Hindlimb; Human; Hyperreflexia; In Vitro; Individual; Injury; Institutes; Institution; Interneurons; Intervention; Iowa; Kinesiology; Knowledge; Laboratories; Learning; Lesion; Location; Measures; Mentors; Mentorship; Modeling; Motor; Motor Neurons; Mus; Muscle; Muscle Contraction; Nanotechnology; Nature; Neurobiology; Neurons; Paralysed; Pathway interactions; Patients; Persons; Pharmacology; Physical therapy; Physiology; Play; Positioning Attribute; Preparation; Rattus; Recovery; Reflex action; Rehabilitation therapy; Research; Research Personnel; Residual state; Role; Sensory; Serotonin; Severities; Smooth Muscle; Spasm; Spinal; Spinal Cord; Spinal Cord transection injury; Spinal Injuries; Spinal cord injury; Spinal cord injury patients; System; Techniques; Testing; Therapeutic Intervention; Time; Translating; Universities; Work; axon regeneration; base; behavior test; career; clinically relevant; design; dorsal horn; embryonic stem cell; experience; experimental study; functional outcomes; improved; in vivo; kinematics; neuronal excitability; neurophysiology; neuroregulation; novel; novel therapeutics; physical therapist; professor; programs; public health relevance; relating to nervous system; sensory stimulus; serotonin receptor; spam

 DESCRIPTION (provided by applicant): My dedication to spinal cord injury (SCI) comes from both my clinical and academic experiences. As a clinician, I specialized in improving the overall function of persons with SCI and teaching other clinicians specialized treatments for SCI. As an academic, I have had extensive and broad research experiences in SCI. I started working in human SCI research first examining bone mineral density changes post injury at the University of Iowa and then studying the spinal circuitry changes occurring post SCI that contribute to spams at the Rehabilitation Institute of Chicago. My experience with human SCI research and my experiences in the clinic prompted my return to academia full-time to use research to improve the lives of individuals with spinal cord injury (SCI) as my main focus. During my PhD with Jack Kessler, MD, my emphasis was toward interventions. I used developmental neurobiological approaches to attenuating or solving SCI including neural and oligodendritic replacement with embryonic stem cells and axon regeneration with growth factors and development-inspired nanotechnology materials. In performing these studies with my experience as a physical therapist, I saw a great need to develop specific quantitative behavioral tests so we can prove not only that our interventions work, but how exactly they contribute to function. My postdoctoral fellowship with Matt Tresch, PhD, aimed at developing such tests. At present, we have pioneered several new techniques for looking at in vivo mouse behaviors including chronic multi-muscle EMG recordings and single motor unit recordings in the mouse. The spectrum of neuroscientific areas and techniques in which I have experience is quite broad, however, the one piece that is missing is the ability to examine neuronal function using cellular electrophysiology. My short-term career goal is to fill this gap. This proposal provides the expertise and protected time for this learning to occur. Once I am able to perform the techniques listed in my proposal and combine these with my previous experimental knowledge and clinical experience, I will be uniquely qualified for my long-term goal of producing a comprehensive, translatable spinal cord injury research program that is based on novel therapeutics and a basic science understanding of how recovery can be improved, not only on a cellular basis, but on a systems basis as well. Mentorship for this award and for the beginning of my career is found here at Northwestern as well as at outside institutions. I began my position as an Assistant Professor in the Departments of Physical Therapy and Human Movement Sciences Physiology at Northwestern University in 2013. The PTHMS and Physiology departments are very supportive of my research, as my position requires at most 20% teaching and research space within the Physiology Department. I have shared space and equipment with my consultant, Matt Tresch, PhD for my proposed in vivo behavioral experiments as well as for space and equipment for the proposed in vitro cellular electrophysiology experiments from my mentor, CJ Heckman, PhD. Again, my goal is always to design my experiments to be as clinically relevant as possible and my clinical experience supports this goal, but my chairperson and consultant Jules Dewald, PT, PhD, will also be evaluating my work for translatability as this is clearly a strength for him. Finally, two outstandng researchers, Ron Harris-Warrick, PhD at Cornell University and Claire Meehan, PhD at the University of Copenhagen will provide mentoring outside of Northwestern. They have both graciously invited me to their laboratories to learn their novel and unique in vitro cellular electrophysiology techniques to answer the questions posed in my proposal. The inception of this proposal started at the beginning of my professional journey when working in human SCI with Brian Schmit, PhD and in the clinic with SCI patients and aims to understand the cellular changes underlying spams after SCI so as to provide better treatments. Spasms are caused by hyperexcitability in both interneurons and motoneurons. Normally, descending neuromodulatory pathways, especially the serotonergic raphespinal system, control excitability of both types of spinal neurons. The loss of this serotonergic input to the spinal cord has several consequences, all of which potentially contribute to spasms following SCI. First, following complete transection, the loss of this serotonergic input to the ventral spinal cord causes motoneurons to increase expression of constitutively active serotonin receptors. This adaptation causes motoneurons to become intrinsically hyperexcitable and to become supersensitive to any residual serotonin. In addition to these effects on ventrally located motoneurons, the loss of raphespinal inputs to the dorsal spinal cord releases interneurons from serotonergic inhibition, increasing interneuron excitability and supersensitivity. Each of these alterations can contribute to the expression of spasms following SCI. However, their specific contributions will depend on the nature of the spinal injury. For example, the supersensitivity of neurons to serotonin might play a smaller role following complete SCI than following incomplete SCI where some residual raphespinal systems remain intact. Similarly, injuries that preferentially affect dorsal or ventral raphespinal systems might differentially involve hyperexcitability in motoneurons or disinhibition of interneurons. Our proposal uses an unparalleled range of unique mouse preparations and novel therapeutics to test how these cellular alterations underlie the variability seen in spasms post SCI and provide directions for therapeutic intervention.

 描述（由申请人提供）：我对脊髓损伤（SCI）的贡献来自我的临床和学术经验。作为一名临床医生，我专注于改善SCI患者的整体功能，并教授其他临床医生SCI的专业治疗方法。作为一名学者，我在SCI方面有着广泛而广泛的研究经验。我开始从事人类脊髓损伤研究，首先在爱荷华州大学检查受伤后的骨矿物质密度变化，然后在芝加哥康复研究所研究脊髓损伤后发生的脊髓回路变化，这些变化导致了垃圾邮件。我在人类SCI研究方面的经验和我在临床上的经验促使我全职回到学术界，利用研究来改善脊髓损伤（SCI）患者的生活。在我和Jack Kessler博士一起读博士期间，我的重点是干预。我使用发育神经生物学方法来减轻或解决SCI，包括用胚胎干细胞替代神经和寡树突，用生长因子和发育启发的纳米技术材料再生轴突。在以我作为物理治疗师的经验进行这些研究时，我看到非常需要开发特定的定量行为测试，这样我们不仅可以证明我们的干预措施有效，而且可以证明它们对功能的贡献。我和马特·特雷施博士的博士后研究旨在开发这样的测试。目前，我们已经开创了几种新的技术来观察在体小鼠的行为，包括慢性多肌肉肌电图记录和单运动单位记录在小鼠。神经科学领域的光谱和技术，我有经验是相当广泛的，然而，缺少的一块是使用细胞电生理学检查神经元功能的能力。我的短期职业目标就是填补这个空白。该提案为这种学习提供了专业知识和保护时间。一旦我能够执行我的建议中列出的技术，并将这些技术与我以前的实验知识和临床经验相结合，我将唯一有资格实现我的长期目标，即制定一个全面的，可翻译的脊髓损伤研究计划，该计划基于新的治疗方法和对如何改善恢复的基础科学理解，不仅在细胞基础上，而且在系统基础上。 导师为这个奖项和我的职业生涯的开始是在这里发现西北以及在外部机构。2013年，我开始在西北大学物理治疗和人体运动科学生理学系担任助理教授。PTHMS和生理学系非常支持我的研究，因为我的职位要求生理学系内最多20%的教学和研究空间。我与我的顾问Matt Tresch博士共享空间和设备，用于我提出的体内行为实验，以及我的导师CJ Heckman博士提出的体外细胞电生理学实验的空间和设备。同样，我的目标始终是将我的实验设计得尽可能与临床相关，我的临床经验也支持这一目标，但我的主席兼顾问Jules Dewald，PT，PhD，也将评估我的工作的可译性，因为这显然是他的优势。最后，两位杰出的研究人员，康奈尔大学的罗恩哈里斯-沃里克博士和哥本哈根大学的克莱尔米汉博士将在西北大学之外提供指导。他们都盛情邀请我去他们的实验室学习他们新颖独特的体外细胞电生理学技术，以回答我的建议中提出的问题。 这个建议的开始是在我与Brian Schmit博士一起研究人类SCI以及在SCI患者诊所工作的职业生涯之初，旨在了解SCI后垃圾邮件背后的细胞变化，以便提供更好的治疗。痉挛是由中间神经元和运动神经元的过度兴奋引起的。正常情况下，下行神经调节通路，特别是多巴胺能中缝脊神经系统，控制这两种类型的脊髓神经元的兴奋性。这种神经递质输入到脊髓的损失有几个后果，所有这些都可能导致SCI后的痉挛。首先，在完全横切后， 这种到腹侧脊髓的多巴胺能输入的损失导致运动神经元增加组成性活性5-羟色胺受体的表达。这种适应导致运动神经元本质上变得过度兴奋，并对任何残留的5-羟色胺变得超敏感。除了对位于腹侧的运动神经元的这些作用之外，向背侧脊髓的中缝脊神经输入的丧失使中间神经元从肾上腺素能抑制中释放，增加中间神经元的兴奋性和超敏性。这些改变中的每一个都有助于SCI后痉挛的表达。然而，它们的具体贡献将取决于脊髓损伤的性质。例如，神经元对5-羟色胺的超敏感性在完全性SCI后可能比在不完全性SCI后发挥更小的作用，在不完全性SCI后，一些残留的中缝棘系统保持完整。同样，优先影响背侧或腹侧中缝棘系统的损伤 可能不同地涉及运动神经元的过度兴奋或中间神经元的去抑制。我们 该提案使用了一系列无与伦比的独特小鼠制剂和新型治疗方法来测试这些细胞改变如何成为SCI后痉挛中观察到的变异性的基础，并为治疗干预提供指导。