Effect of Injury Severity and Location on Spasms Post SCI

 描述(申请人提供)：我对脊髓损伤(SCI)的执着来自于我的临床和学术经验。作为一名临床医生，我专门致力于改善脊髓损伤患者的整体功能，并向其他临床医生传授脊髓损伤的专门治疗方法。作为一名学者，我在SCI方面有广泛的研究经验。我开始从事人类脊髓损伤的研究，首先在爱荷华大学检查损伤后骨密度的变化，然后在芝加哥康复研究所研究脊髓损伤后脊髓回路的变化，这些变化导致垃圾邮件的产生。我在人类脊髓损伤研究方面的经验和我在诊所的经历促使我全职回到学术界，利用研究来改善以脊髓损伤(SCI)为主要关注点的个人生活。在我攻读杰克·凯斯勒医学博士期间，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脊髓损伤，包括用胚胎干细胞替代神经和少树突状细胞，以及用生长因子和受发育启发的纳米材料再生轴突。在以我作为理疗师的经验进行这些研究时，我意识到非常有必要开发具体的定量行为测试，以便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确切贡献。我与马特·特雷什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观察小鼠体内行为的新技术，包括慢性多肌肉肌电记录和小鼠单运动单位记录。我有经验的神经科学领域和技术的光谱相当广泛，然而，缺少的一部分是使用细胞电生理学检查神经元功能的能力。我的短期职业目标是填补这一空白。这项建议为这种学习提供了专业知识和受保护的时间。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，即制作一个全面的、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康复的基本科学理解，不仅在细胞基础上，而且在系统基础上。这一奖项和我职业生涯的开始都得到了西北大学和外部机构的指导。2013年，我开始在西北大学物理治疗系和人体运动科学生理学系担任助理教授。PTHMS和生理系非常支持我的研究，因为我的职位最多需要生理系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，用于我提议的活体行为实验，以及我的导师CJ Heckman博士提议的体外细胞电生理学实验的空间和设备。同样，我的目标总是设计我的实验尽可能地与临床相关，我的临床经验支持这一目标，但我的主席兼顾问Jules Dewald，PT，博士，也将评估我的工作的可译性，因为这显然是他的优势。最后，康奈尔大学的Ron Harris-Warrick博士和哥本哈根大学的Claire Meehan博士这两位杰出的研究人员将在西北大学以外的地方提供指导。他们都热情地邀请我到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，以回答我在提案中提出的问题。这项建议始于我与Brian Schmit博士在人类脊髓损伤中工作的职业旅程的开始，以及在与SCI患者的诊所中的工作，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5-羟色胺能神经系统，控制着这两种类型脊髓神经元的兴奋性。脊髓5-羟色胺能输入的丧失有几个后果，所有这些都可能导致脊髓损伤后的痉挛。首先，在完全横切后， 5-羟色胺能传入腹侧脊髓的缺失会导致运动神经元增加结构性活性5-羟色胺受体的表达。这种适应使运动神经元本能地变得高度兴奋，并对任何残留的5-羟色胺变得超级敏感。除了对腹侧运动神经元的这些影响外，失去对背侧脊髓的神经传入也会将中间神经元从5-羟色胺能抑制中释放出来，增加神经元间的兴奋性和超敏性。这些改变中的每一个都可能导致脊髓损伤后痉挛的表达。然而，他们的具体贡献将取决于脊柱损伤的性质。例如，在完全性脊髓损伤后，神经元对5-羟色胺的超敏反应可能比部分残存神经系统完好无损的不完全性脊髓损伤所起的作用要小。同样，优先影响背侧或腹侧神经系统的损伤 可能涉及运动神经元的过度兴奋或中间神经元的去抑制。我们的 Proposal使用了一系列无与伦比的独特的小鼠制剂和新的疗法来测试这些细胞变化是如何导致脊髓损伤后痉挛的变异性，并为治疗干预提供方向。

 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.