Demyelination Plus Transplantation to Study CNS Repair

脱髓鞘加移植研究中枢神经系统修复

• 批准号: 6622039
• 负责人: HANS S KEIRSTEAD
• 金额: $ 21.07万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6622039
• 关键词: Schwann cells; astrocytes; axon; bromodeoxyuridine; cell transplantation; central nervous system; cerebrosides; complement; dorsal column; glial fibrillary acidic protein; histology; hypertrophy; immunocytochemistry; in situ hybridization; laboratory rat; leukocyte activation /transformation; macrophage; myelinopathy; nervous system regeneration; nervous system transplantation; neuronal transport; nonhuman therapy evaluation; peripheral nervous system; spinal cord injury; tissue /cell preparation

Demyelination represents a unique injury to the adult CNS in that it is followed in many instances by repair. Regions of demyelination that are capable of remyelinating are not characterized by an astroglial scar. We have demonstrated that regions of immunological demyelination, produced by the intraspinal injection of anti-galactocerebroside antibodies plus complement proteins, are capable of remyelination by endogenous oligodendrocytes, and that astroglial hypertrophy is absent within and around regions of immunological demyelination. Furthermore, our preliminary studies indicate that astrocytes within regions of immunological demyelination do not become hypertrophic following axonal injury. Thus, immunological demyelination provides us with a means to manipulate the response of reactive cells to axonal injury and investigate the ways in which that response differs from that following the majority of CNS injuries, which result in scarring. We will use integrated optical density measurements to determine whether the astrocyte and/or microglial/macrophage response to injury is eliminated, suppressed or delayed by immunological demyelination. These studies, which constitute the last two AIMS of this proposal, may lead to novel means of manipulating astrocytes such that astroglial activation or scarring is prevented. Likely associated with the absence of astroglial hypertrophy, regions of immunological demyelination promote long distance homogeneous redistribution of transplanted cells throughout the region of immunological demyelination. This provides a unique opportunity to create a PNS-like terrain within the CNS that is not bordered by an astroglial scar. This experimental paradigm allows us to study the ability to injured axons to regenerate from such a PNS-like terrain into the CNS environment without confronting a sclerotic border zone. Our regenerative analysis will be conducted using anterograde tract tracing. These studies constitute the first AIM of this proposal. There are three specific aims; 1) test the hypothesis that regenerating dorsal column axons will extend from a PNS-like terrain into a purely CNS terrain in the absence of scarring at the interface, 2) test the hypothesis that immunological demyelination suppresses astroglial hypertrophy following axonal injury, and 3) test the hypothesis that immunological demyelination alters the magnitude and duration of microglial/macrophage activation following axonal injury.

脱髓鞘是一种独特的损伤成人中枢神经系统，因为它是随后在许多情况下修复。 能够再生髓鞘的脱髓鞘区域不以星形胶质细胞瘢痕为特征。 我们已经证明，免疫脱髓鞘，脊髓内注射抗半乳糖苷抗体加补体蛋白，产生的区域能够髓鞘再生的内源性少突胶质细胞，和星形胶质细胞肥大是不存在的免疫脱髓鞘区域内和周围。此外，我们的初步研究表明，免疫脱髓鞘区域内的星形胶质细胞不会成为轴突损伤后肥大。 因此，免疫脱髓鞘为我们提供了一种手段来操纵反应性细胞对轴突损伤的反应，并研究该反应与导致瘢痕形成的大多数CNS损伤后的反应不同的方式。 我们将使用积分光密度测量，以确定是否星形胶质细胞和/或小胶质细胞/巨噬细胞对损伤的反应被消除，抑制或延迟免疫脱髓鞘。 这些研究构成了该提案的最后两个目标，可能会导致操纵星形胶质细胞的新方法，从而防止星形胶质细胞活化或瘢痕形成。可能与星形胶质细胞肥大的不存在相关，免疫脱髓鞘区域促进移植细胞在整个免疫脱髓鞘区域的长距离均匀再分布。 这提供了一个独特的机会，在CNS内创建一个不以星形胶质细胞疤痕为边界的类似PNS的地形。 这种实验范式使我们能够研究损伤轴突从这种类似PNS的地形再生到CNS环境中而不面对scaffold边界区的能力。 我们的再生分析将使用顺行追踪进行。 这些研究构成了本提案的第一个目标。具体目标有三个：1）检验再生的背柱轴突将在界面处没有瘢痕形成的情况下从PNS样区延伸到纯CNS区的假设，2）检验免疫脱髓鞘抑制轴突损伤后星形胶质细胞肥大的假设，和3）检验免疫脱髓鞘改变轴突损伤后小胶质细胞/巨噬细胞活化的幅度和持续时间的假设。