Factors Affecting Regeneration Through the Glial Scar

影响神经胶质疤痕再生的因素

基本信息

批准号：
7406769
负责人：
Jerry Silver
金额：
$ 33.55万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-02-01 至 2009-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): We have developed a new in vitro model of the glial scar in which inhibitory CS-PG in a crude gradient more closely resembles that which occurs in vivo after injury. Classic dystrophic endballs form at the tips of adult sensory axons that become trapped within the gradient. We can now ask, for the first time, a variety of basic questions concerning the biology of the dystrophic growth cone. Three important questions we wish to pursue in aim 1 are: (A) whether the dystrophic state is a peculiarity of adult neurons, (B) whether CNS neurons would respond similarly to the PG gradient environment and, (C) whether dendrites respond differently to the inhibitory gradient than do axons. Finally, (D) we would like to know what molecular changes occur in would- be dystrophic axons that are induced to regrow across the potently inhibitory rim of the gradient via a new combinatorial regeneration stimulating strategy. Our ultimate goal is to devise an optimal strategy in vitro that can be used to overcome growth cone dystrophy and stimulate axon regeneration past the glial scar in vivo. In aim 2, preliminary in vivo results based on a successful regeneration promoting strategy using our in vitro gradient model, have shown evidence that a combination of chronic sterile inflammation induced in the DRG prior to root crush, plus chondroitinase application to the root entry zone at the time of crush, can foster robust regeneration of sensory axons into the spinal cord. We hypothesize that a similar strategy may foster sensory fiber regeneration in a more clinically relevant post-injury model. We propose to study the functional efficacy of these fibers. In aim 3, we will utilize a novel microlesion model of the cingulum in which one can make the smallest lesion possible but still clearly identify only those axons that have been severed and have potentially regenerated. With the microlesion model, we can use the micropipette, that cuts the axons, to inject bridge building cells or other factors upon withdrawal of the pipette from the brain. Preliminary evidence shows that injection of chondroitinase combined with immature astroglia can stimulate regeneration clearly past the lesion. None-the-less, once past the lesion the fibers only grow short distances. Using this model we hypothesize that by also driving the intrinsic growth potential of the regenerating neurons at the vicinity of their cell body, regeneration will be significantly enhanced.

描述（由申请人提供）：我们已经开发了一种新的胶质疤痕体外模型，在该模型中，粗梯度中的抑制性CS-PG更相似地相似于受伤后体内发生的抑制作用。经典的营养不良的末日在被困在梯度内的成年感觉轴突的尖端形成。现在，我们可以首次提出有关营养不良生长锥生物学的各种基本问题。我们希望在AIM 1中提出的三个重要问题是：（a）营养不良状态是否是成人神经元的特殊性，（b）CNS神经元是否对PG梯度环境的反应是否类似，并且（C）树突对抑制性梯度的反应是否与Axons相似。最后，（d）我们想知道可能是营养不良的轴突中发生的分子变化，这些变化是通过新的组合再生刺激策略引起的，这些轴突被诱导会在梯度的有效抑制作用上再生。我们的最终目标是在体外设计一种最佳策略，该策略可用于克服生长锥体营养不良，并刺激体内神经胶质疤痕的轴突再生。在AIM 2中，基于使用我们的体外梯度模型的成功再生策略促进策略的初步体内结果表明，证据表明，在根挤压之前，在DRG中诱导的慢性无菌炎症的结合，加上软骨素酶在压迫时将软骨蛋白酶应用于crumper时，可以促进感官轴突的稳健再生脊柱的稳健再生。我们假设类似的策略可以在更临床相关的伤害后模型中促进感觉纤维再生。我们建议研究这些纤维的功能功效。在AIM 3中，我们将利用一种新型的扣可扣微作用模型，在该模型中，人们可以使最小的病变成为可能，但仍然清楚地仅识别那些已被切断并可能再生的轴突。借助微型模型，我们可以使用切割轴突，从大脑撤离移液器后的桥梁建筑单元或其他因素的微型移动物。初步证据表明，将软骨素酶与未成熟的星形胶质细胞结合的注射可以清楚地刺激病变后的再生。尽管如此，一旦经过病变，纤维只会长短距离。使用该模型，我们假设通过推动其细胞体附近再生神经元的内在生长潜力，再生将显着增强。