PREVENTION OF DENDRITIC ATROPHY AFTER MOTONEURON INJURY

运动神经元损伤后树突萎缩的预防

• 批准号: 7437371
• 负责人: DALE R SENGELAUB
• 金额: $ 19.23万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7437371
• 关键词: Adult; Androgens; Animal Model; Animals; Atrophic; Axotomy; Brain-Derived Neurotrophic Factor; Castration; Cellular Structures; Cessation of life; Dendrites; Development; Disease; Dose; Gonadal Steroid Hormones; Implant; In Situ Hybridization; Injury; Methods; Modeling; Morphology; Motor; Motor Neurons; Muscle; Nerve; Neurodegenerative Disorders; Neurotrophic Tyrosine Kinase Receptor Type 2; Pathology; Peripheral; Peripheral Nerves; Peripheral nerve injury; Physiological; Plasma; Prevention; Principal Investigator; Range; Rattus; Recovery; Recovery of Function; Role; Spinal; Spinal Cord; Spinal Cord Diseases; Spinal cord damage; Techniques; Testing; Testosterone; Therapeutic; Therapeutic Effect; Time; Transgenic Animals; Work; combinatorial; functional restoration; improved; injured; male; nerve injury; neurotrophic factor; prevent; programs; receptor; reinnervation; research study; restoration; steroid hormone

DESCRIPTION (provided by applicant): Neurodegenerative diseases or nerve injury can result in the loss of spinal motoneurons. However, remaining motoneurons after such insults show a variety of morphological and functional changes. As a consequence of both the loss of some motoneurons and the secondary changes in other, remaining motoneurons, functional restoration is poor, and the time course of recovery is protracted at best. The development of animal models, for example involving direct spinal cord damage or peripheral nerve injury, have begun to yield clues to both the mechanisms involved in motoneuron pathology and potential therapeutic approaches. Our work will concentrate on motoneuron dendrites, which are essential for the reception and integration of information. Dendrites in motoneurons atrophy after nerve injury or the death of neighboring motoneurons, and preventing that atrophy, or improving its recovery, in motoneurons that survive the initial insult will have a major impact on the restoration of spinal function. We have begun to develop two models in the adult rat spinal cord, utilizing induced motoneuron death or peripheral nerve cuts that will allow us to examine potential ways of preventing, or accelerating recovery from, dendritic atrophy in remaining motoneurons. In our first model, we found that the death of neighboring motoneurons causes the dendritic arbor of the remaining motoneurons to atrophy, but that manipulation of steroid hormones, specifically testosterone, can prevent or reverse that atrophy. Using morphological methods, we will determine if there is a dose/effect relationship for testosterone and dendritic protection, and if so, establish the minimum amount of testosterone required. We will also test the degree of functional recovery produced by these manipulations using electrophysiological methods. Using morphological methods, we will determine if there are critical temporal limits to the therapeutic window for protection from dendritic atrophy, and whether androgen prevents or accelerates recovery from dendritic atrophy. In our second model, we found an interactive effect of testosterone with brain-derived neurotrophic factor (BDNF) in preventing dendritic atrophy after cutting peripheral motor nerves. We will test whether the expression of BDNF in muscle or motoneurons, or its receptors, could be regulated by androgens, utilizing in situ hybridization and immunohistochemical techniques Together, results from studies using these two models will be informative about the therapeutic role for steroid hormones in treating spinal cord disease or nerve injury.

描述（由申请人提供）：神经退行性疾病或神经损伤可能导致脊髓运动神经元的损失。然而，这种损伤后剩余的运动神经元表现出各种形态和功能的变化。由于一些运动神经元的损失和其他剩余运动神经元的继发性变化，功能恢复很差，并且恢复的时间充其量是延长的。动物模型的发展，例如涉及直接脊髓损伤或周围神经损伤的动物模型，已经开始为运动神经元病理学涉及的机制和潜在的治疗方法提供线索。我们的工作将集中在运动神经元树突上，它对于信息的接收和整合至关重要。神经损伤或邻近运动神经元死亡后，运动神经元中的树突萎缩，而在最初损伤后幸存下来的运动神经元中防止萎缩或改善其恢复将对脊髓功能的恢复产生重大影响。我们已经开始在成年大鼠脊髓中开发两种模型，利用诱导运动神经元死亡或周围神经切断，这将使我们能够研究预防剩余运动神经元树突状萎缩或加速其恢复的潜在方法。在我们的第一个模型中，我们发现邻近运动神经元的死亡导致剩余运动神经元的树突乔木萎缩，但是类固醇激素（特别是睾酮）的操纵可以预防或逆转这种萎缩。使用形态学方法，我们将确定睾酮和树突保护是否存在剂量/效应关系，如果是，则确定所需的最小睾酮量。我们还将使用电生理学方法测试这些操作产生的功能恢复程度。使用形态学方法，我们将确定防止树突萎缩的治疗窗口是否存在关键的时间限制，以及雄激素是否可以预防或加速树突萎缩的恢复。在我们的第二个模型中，我们发现睾酮与脑源性神经营养因子（BDNF）之间存在相互作用，可以预防切断周围运动神经后的树突萎缩。我们将利用原位杂交和免疫组织化学技术，测试肌肉或运动神经元或其受体中 BDNF 的表达是否可以受到雄激素的调节。使用这两种模型的研究结果将有助于了解类固醇激素在治疗脊髓疾病或神经损伤中的治疗作用。