Cervical spinal injury and demyelination in aged rats

描述(申请人提供)：脊髓损伤(SCI)的人口统计正在发生变化，越来越多的老年人脊髓损伤出现在急诊室，特别是与跌倒相关的颈椎SCI(Ho等，2007)。此外，衰老还与脊椎病和颈椎管狭窄有关。由此产生的慢性压迫被认为与包括脱髓鞘在内的缓慢神经退行性变化有关，即使没有急性损伤也会导致功能丧失。脊椎病和椎管狭窄也增加了与跌倒相关的挫伤损伤的可能性。衰老也会影响髓鞘形成和再髓鞘形成的能力(例如，Peters和Sethares，2003)，而且有证据表明，随着年龄的增长，中枢神经系统本身可能更容易受到损伤，对损伤的可塑性可能会降低。这两个因素都可能导致复苏放缓。我们认为，这种易感性的增加可能部分是由于少突胶质细胞系的内源性成体神经胶质前体细胞对损伤的修复反应发生了变化，其特征是PDGFR1和蛋白多糖NG2的表达(见Horner等人，2002；Polito和Reynolds，2006；Rhodes等人，2006)。在目标1中，我们将建立一种慢性颈椎压迫的模型，该模型会在年轻、成年的Fischer 344xBN杂交大鼠中产生进行性神经功能障碍和脱髓鞘。随后将对大鼠进行一系列神经结果测量，包括前肢运动功能测试和感觉变化(如超感和疼痛)的发展测试。脊髓损伤、脱髓鞘和重新髓鞘形成的组织学特征将在尸检后进行。在目标2和目标3中，我们将使用目标1中开发的模型来测试衰老导致对慢性颈椎压迫的易感性的假设，并询问衰老的影响是由于对少突胶质细胞和轴突死亡的易感性增加，以及祖细胞修复和再髓鞘形成减少，还是两者的结合。我们还假设，幼鼠和老年鼠在炎症反应方面的差异可能起到一定作用。我们将使用行为学和组织学结果测量方法比较年轻(3个月)、中年(9个月)和老年(15个月)大鼠对慢性压迫损伤的反应。如果在衰老过程中发现修复反应不足或减少，我们将在未来的研究中测试恢复或替换祖细胞群体的治疗方法，以改善这种缺陷。脊髓损伤(SCI)目前在老年人群中的发病率越来越高，可由急性损伤引起，也可由年龄相关性关节炎和脊髓压迫引起的慢性颈髓脊髓病引起。这项建议的工作将使用大鼠损伤模型来检验成体干细胞群体、少突胶质细胞前体细胞(OPC)在脊髓病的发展中的作用以及在脊髓损伤后衰老恢复中的作用。预计这一结果将有助于开发改善老年人类神经功能的疗法。

DESCRIPTION (provided by applicant): The demographic of spinal cord injury (SCI) is changing, with more and more aged individuals showing up at emergency rooms with spinal cord injuries, especially cervical SCIs related to falls (Ho et al, 2007). In addition, aging is associated with spondylosis and narrowing of the cervical spinal canal. The resultant chronic compression is thought to be associated with slow neurodegenerative changes including demyelination, resulting in loss of function even without a precipitating acute injury. Spondylosis and stenosis also increase the probability of contusion injury associated with falls. Aging also affects myelination and the capacity for remyelination (e.g. Peters and Sethares, 2003) and there is evidence that the CNS itself may be more vulnerable to injury with aging and may have a less plastic response to injury. Both factors could lead to less recovery. Here we propose that that increased vulnerability may be due in part to changes in the reparative response to injury mounted by endogenous adult glial progenitor cells of the oligodendrocyte lineage, which are characterized by the expression of the PDGFR1 and the proteoglycan NG2 (see Horner et al, 2002; Polito and Reynolds, 2006; Rhodes et al, 2006). In Aim 1. we will establish a model of chronic cervical compression that produces progressive neurological deficits and demyelination in young, adult Fischer 344xBN hybrid rats. Rats will be followed with a panel of neurological outcome measures, including forelimb motor function tests and tests for the development of altered sensation (e.g. allodynia and pain). Histological characterization of cord damage, demyelination and remyelination will be made post-mortem. In Aims 2 and 3, we will use the model developed in aim 1 to test the hypothesis that aging results in a greater susceptibility to chronic cervical compression, and ask if the effects of aging are due to increased susceptibility to oligodendrocyte and axonal death, and reduced progenitor cell repair and remyelination, or a combination. We also hypothesize that differences in the inflammatory response in young vs. old rats may play a role. We will compare the responses of young (3 months), middle aged (9 months) and old (15 months) rats to chronic compression injury using both behavioral and histological outcome measures. If the repair response is found to be deficient or reduced in aging, in future studies we will test treatments to reinvigorate or replace the progenitor cell population to ameliorate the deficits. PUBLIC HEALTH RELEVANCE Spinal cord injury (SCI) is now occurring more and more in the aged population, and can be due to acute injury, or the kinds of chronic cervical spinal cord myelopathy that occurs due to age-related arthritis and cord compression. The work proposed here will examine the role of a population of adult stem cells, oligodendrocyte progenitor cells (OPCs) in the development of myelopathy, and in recovery after SCI in aging using rat models of injury. It is expected that the results will contribute to the development of therapies that will improve neurological function in aging humans.