MECHANISMS OF INJURY POTENTIATION BY GROWTH FACTORS

描述(改编自申请人的摘要)：多个神经元 种群，生长因子减轻由各种不同的 侮辱。由于生长因子具有广泛的保护作用，它们 目前被认为是治疗中风的潜在药物， 肌萎缩侧索硬化症、帕金森氏病等神经退行性疾病 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一直令人失望。 此外，尽管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 多项研究表明，生长因子对损伤有促进作用。这个 在本提案中要检验的假设是，在特定的定义下， 在条件允许的情况下，许多生长因子都会对损伤产生增强作用。 初步数据显示，虽然增长因素持续 对诱导细胞凋亡的侮辱具有保护作用，它们增强了 某些形式的坏死性细胞死亡。因此，为了最大限度地发挥治疗作用 生长因子的有用性有必要通过以下方法确定其作用机制(S) 其中发生了增强损伤的作用。增长机制研究(S) 细胞死亡的因子增强将侧重于扩大初步结果 这表明了线粒体自由基形成增加的作用， 钙离子内流增加，神经递质释放改变。初步 研究主要集中在脑源性神经营养因子对血管生成的影响。 大脑皮层培养中的缺氧糖。拟议的实验将使用 从选定的大脑区域制备的神经元培养，并具有特定的 生长因子，每一种都是因为已知的细胞死亡和 与疾病状况的相关性。人们相信，这些研究将有助于 确定生长因子在什么条件下诱导细胞增强 死亡可能会引起人们对它们的治疗用途的关注，以及这些担忧是如何 可能会被解决。

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.