Cervical spinal injury and demyelination in aged rats

描述（由申请人提供）：脊髓损伤（SCI）的人口统计学正在发生变化，越来越多的老年人因脊髓损伤出现在急诊室，尤其是与福尔斯相关的颈椎SCI（Ho等人，2007）。此外，老化与颈椎病和颈椎管狭窄有关。由此产生的慢性压迫被认为与缓慢的神经退行性变化相关，包括脱髓鞘，导致功能丧失，即使没有急性损伤。脊椎病和狭窄也增加了与福尔斯有关的挫伤的可能性。衰老也会影响髓鞘形成和髓鞘再生能力（例如Peters和Sethares，2003），有证据表明，随着衰老，CNS本身可能更容易受到损伤，对损伤的塑性反应可能更少。这两个因素都可能导致复苏放缓。在此，我们提出，脆弱性增加可能部分是由于对由少突胶质细胞谱系的内源性成体神经胶质祖细胞引起的损伤的修复反应的变化，其特征在于PDGFR 1和蛋白聚糖NG 2的表达（参见Horner等人，2002; Polito和Reynolds，2006;罗兹等人，2006）。在目标1中。我们将在年轻的成年Fischer 344 xBN杂种大鼠中建立慢性颈部压迫模型，该模型产生进行性神经功能缺损和脱髓鞘。将对大鼠进行一组神经学结局测量，包括前肢运动功能试验和感觉改变（例如异常性疼痛和疼痛）发生试验。将在死后进行脊髓损伤、脱髓鞘和髓鞘再生的组织学表征。在目标2和3中，我们将使用目标1中开发的模型来检验衰老导致对慢性颈椎压迫的更大易感性的假设，并询问衰老的影响是否是由于对少突胶质细胞和轴突死亡的易感性增加，以及祖细胞修复和髓鞘再生减少，或组合。我们还假设年轻大鼠与老年大鼠炎症反应的差异可能起作用。我们将比较年轻（3个月），中年（9个月）和老年（15个月）大鼠慢性压迫损伤的反应，使用行为和组织学结果的措施。如果发现修复反应在衰老中缺乏或减少，在未来的研究中，我们将测试治疗方法，以重振或取代祖细胞群体，以改善缺陷。公共卫生相关性脊髓损伤（SCI）现在越来越多地发生在老年人群中，可能是由于急性损伤，或由于年龄相关性关节炎和脊髓压迫而发生的慢性颈脊髓脊髓病。本文提出的工作将使用大鼠损伤模型研究成体干细胞、少突胶质祖细胞（OPCs）在脊髓病发展中的作用，以及在脊髓损伤后的衰老恢复中的作用。预计这些结果将有助于开发改善老年人神经功能的疗法。

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.