Interactions between Urological and Locomotor Systems during Treadmill Training i

描述(申请人提供)：脊髓损伤(SCI)会对上尿路和下尿路造成不利影响。目前还没有有效的治疗泌尿系统功能障碍的方法。对排尿功能的控制对这一患者群体至关重要，因为这会影响独立性、整体健康和自我形象。目前用各种药物和手术治疗的尝试都有不想要的副作用和有限的成功。我们的目标之一是提供一种天然的治疗替代方案。体重支持的跑步机训练正在推动我们对脊髓如何学习和适应的了解，其对脊髓损伤患者的积极影响的结果继续增长。我们从患者的临床观察中发现，阶梯训练对膀胱维护有好处，而且四肢和膀胱之间存在抑制相互作用。因此，我们建议在临床相关的动物模型中研究这些观察结果，以确定相关的机制。86只雄性大鼠将使用IH冲击器或装置在T8脊柱水平上受到225kdyn力的挫伤。在26只大鼠的比目鱼肌和胫前肌中植入膀胱导管和肌电丝，以确定在完整、脊髓损伤和炎症条件下，有害和无害的膀胱传入对运动(膀胱-躯体)功能的影响。C-纤维输入的作用也将通过辣椒素的预处理来确定。来自膀胱的炎症和扩张可能改变了腰骶髓的感觉输入，进而改变了运动输出和脊柱学习的能力。从伤后14天开始，20只大鼠每天在跑步机上进行8周的手动踏步训练。另外两组前肢训练组(n=20)和未训练组(n=20)将同时接受测试。通过1)有意识的膀胱测压-导管注入生理盐水和2)使用新陈代谢监测系统收集的自然排尿模式，将获得功能性泌尿学数据。脊髓损伤后11周的末端分子研究将评估运动对各种神经营养因子的膀胱mRNA含量的调节，这些神经营养因子在运动和膀胱功能障碍文献中都被确认为重要的调节因子。因此，本研究将首次探讨运动疗法对逼尿肌、外括约肌和四肢肌肉的内脏和躯体结构之间脊髓介导的反射关系的影响。虽然在正常受试者中这些反射部分被掩盖，但在上运动神经元病或脊髓损伤后，这些反射非常明显。这项研究的每一部分都专门设计成适用于脊髓损伤患者和基于活动的治疗方法，如运动训练。 公共卫生相关性：四肢瘫痪患者和截瘫患者都将膀胱功能列为影响其生活质量的最重要因素之一，在681名受访者中，96.5%的人认为锻炼是功能恢复的重要组成部分，但至少63.6%的人无法找到训练有素的治疗师来监督他们的团。仅在美国就有100多万人受到脊髓损伤的影响，每年联邦基金的成本估计为97亿美元，我们从运动训练对膀胱功能影响的研究中获得的知识不仅立即适用于患者，极大地提高了生活质量，而且还减轻了患者、家庭和护理中心的终身负担。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in detrimental effects on the upper and lower urinary tract. Currently there is no effective therapy for urological dysfunction. Having control over voiding function is of primary importance to this patient population as this affects independence, overall health, and self-image. Current attempts at treatments with various drugs and surgeries have unwanted side effects and limited success. One of our goals is to provide a natural therapeutic alternative. Body weight supported treadmill training is advancing our knowledge on how the spinal cord can learn and adapt, and the results of its positive effects for SCI patients continues to grow. We have clinical observations from patients that step training can have beneficial outcomes on bladder maintenance and that there is an inhibitory interaction between the limbs and the bladder. Therefore, we propose to study these observations in a clinically relevant animal model to identify mechanisms involved. Eighty-six male rats will receive a 225 kdyn force contusion injury at the T8 spinal level using the IH impact or device. Twenty-six rats will be implanted with a bladder catheter and EMG wires in the soleus and tibialis anterior muscles to determine the influence of noxious and innocuous bladder afferent input on locomotor (vesico-somatic) performance in intact, SCI, and inflammatory conditions. The role of C-fiber inputs will also be determined via capsaicin pre-treatment. Inflammation and distention from bladder may be altering sensory inputs for the lumbosacral cord, in turn altering the ability for locomotor output and spinal learning. Beginning 14 days post-injury, twenty rats will undergo daily step training on a treadmill with manual assistance for 8 weeks. Two other groups forelimb trained (n=20) and non-trained (n=20) will be tested simultaneously. Functional urological data will be obtained with 1) conscious cystometry- catheter infused saline and 2) natural voiding patterns gathered using a metabolic monitoring system. Terminal molecular studies eleven weeks post- SCI will assess the exercise's regulation of bladder mRNA content of various neurotrophic factors, which have been identified as important modulators in both the exercise and bladder dysfunction literature. Thus, this study will be the first to investigate the influence of exercise therapy on the spinally mediated reflexive relationship between viscera and somatic structures involving detrusor, external urethral sphincter, and limb musculature. Although partially masked in normal subjects, these reflexes are highly apparent after an upper motor neuron disease or SCI. Each part of this study is specifically designed to be applicable to the SCI patient and activity based therapies such as locomotor training. PUBLIC HEALTH RELEVANCE: Both quadriplegics and paraplegics rank bladder function as one of the most important factors affecting their quality of life, and 96.5% of 681 survey respondents believe that exercise is an important part of functional recovery yet at least 63.6% do not have access to a trained therapist to oversee their regiments. With over 1 million people in the U.S. alone affected by SCI and the annual cost in federal funds estimated at $9.7 billion, the knowledge gained from our study on locomotor training effects on bladder function will not only be immediately applicable to patients, providing immense improvements in quality of life, but also reduce life-long burdens on patient, family, and care centers.