MECHANISMS OF INJURY POTENTIATION BY GROWTH FACTORS

描述（改编自申请人的摘要）：在多个神经元 群体，生长因子减弱由多种细胞因子诱导的细胞死亡。 侮辱。由于生长因子具有广泛的保护作用， 目前被认为是中风的潜在治疗剂， 肌萎缩侧索硬化症、帕金森病和其他神经退行性疾病 条件然而，到目前为止，由于各种原因， 使用神经营养因子的临床试验令人失望。 此外，虽然大多数体外和动物研究表明， 生长因子对神经细胞死亡的影响，也有一个 许多研究表明生长因子的损伤增强作用。的 本提案中要检验的假设是，在具体可界定的 在某些条件下，许多生长因子将具有损伤增强作用。 初步数据表明，虽然生长因子一直 保护免受损伤，诱导凋亡细胞死亡，他们加强 某些形式的坏死细胞死亡。因此，为了最大限度地提高治疗效果， 生长因子的有用性，有必要通过以下方式确定机制： 从而产生损伤增强效应。增长机制研究 因子增强细胞死亡将集中在扩大初步结果 这表明线粒体自由基形成增加的作用， 增加了钙离子的流入，改变了神经递质的释放。初步 研究集中在脑源性神经营养因子对 皮层培养物中的氧-葡萄糖剥夺。拟议的实验将使用 从选定的脑区域制备的神经元培养物， 生长因子，每一种都是因为已知的细胞死亡机制而选择的， 与疾病状况相关。相信这些研究将有助于 确定在何种条件下生长因子诱导细胞增强 死亡可能与其治疗用途有关，以及这些问题 可以解决。

DESCRIPTION (adapted from applicant's abstract): In multiple neuronal populations, growth factors attenuate cell death induced by a variety of insults. Because of the wide range of protective effects of growth factors they are currently being considered as potential therapeutic agents for stroke, amyotrophic lateral sclerosis, Parkinson's disease, and other neurodegenerative conditions. However, to date, and for a variety of reasons, the results of clinical trials using neurotrophic factors have been disappointing. Furthermore, while most in vitro and animal studies have shown protective effects of growth factors against neuronal cell death, there have also been a number of studies showing injury enhancing effects of growth factors. The hypothesis to be tested in this proposal is that, under specific definable conditions, many growth factors will have injury potentiating effects. Preliminary data indicates that while growth factors are consistently protective against insults, which induce apoptotic cell death, they potentiate some forms of necrotic cell death. It follows that to maximize the therapeutic usefulness of growth factors it is necessary to determine the mechanism(s) by which the injury enhancing effects occur. Study of the mechanism(s) of growth factor potentiation of cell death will focus on expanding preliminary results which suggest a role for increased mitochondrial free radical formation, increased calcium influx, and altered neurotransmitter release. Preliminary studies have focused on the effects of brain derived neurotrophic factor on oxygen-glucose deprivation in cortical cultures. Proposed experiments will use neuronal cultures prepared from selected brain regions, and with specific growth factors, each chosen because of known mechanisms of cell death and relevance to disease conditions. It is believed that these studies will aid in determining under what conditions growth factor induced potentiation of cell death may be of concern regarding their therapeutic use, and how those concerns may be addressed.