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: 7237899
• 负责人: DALE R SENGELAUB
• 金额: $ 19.32万
• 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/7237899
• 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导致脊髓运动神经元丢失。然而，这种侮辱后，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运动神经元的继发性变化，功能恢复很差，恢复的时间过程充其量是延长的。动物模型的发展，例如涉及直接脊髓损伤或外周神经损伤，已经开始产生运动神经元病理学机制和潜在治疗方法的线索。我们的工作将集中在运动神经元树突，这是必不可少的接收和整合信息。运动神经元中的树突在神经损伤或邻近运动神经元死亡后萎缩，并且在最初损伤后存活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，利用诱导的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中的树枝状萎缩或加速其恢复的潜在方法。在我们的第一个模型中，我们发现相邻运动神经元的死亡会导致剩余运动神经元的树突萎缩，但类固醇激素的操纵，特别是睾酮，可以防止或逆转这种萎缩。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，则确定所需睾酮的最小量。我们也将测试的程度功能恢复产生这些操作使用电生理方法。使用形态学的方法，我们将确定是否有关键的时间限制的治疗窗口保护树突状萎缩，以及雄激素是否阻止或加速恢复树突状萎缩。在我们的第二个模型中，我们发现了睾酮与脑源性神经营养因子（BDNF）在防止切断外周运动神经后树突萎缩方面的相互作用。我们将测试是否BDNF在肌肉或运动神经元，或其受体的表达，可以调节雄激素，利用原位杂交和免疫组织化学技术。总之，使用这两种模型的研究结果将提供有关类固醇激素在治疗脊髓疾病或神经损伤的治疗作用的信息。