How does the p75 neurotrophin receptor transmit both pro-survival and pro-apoptotic signals in neurons?

两种NGF受体TrkA和p75的信号传导决定了感觉神经元和参与记忆和学习的某些脑神经元的存活或死亡。这些受体最令人困惑的方面是，在大多数情况下，当NGF存在时，它们相互合作以最大限度地提高神经元的存活率，但在某些情况下，它们相互对立。在后一种情况下，NGF治疗可能导致神经元死亡，而不是拯救。在过去的三年中，我们已经开发了新的反义寡核苷酸，可以用来分别关闭每个受体。这些已经是，并将继续是我们研究的特别有价值的工具。我们还发现了两种受体相互作用的新方式（通过称为SHC的信号转导分子），这为我们在这一领域提供了竞争优势。我们有专业知识和设备来识别和克隆缺失的因子，这些因子解释了p75和TrkA之间的矛盾相互作用。该项目的成功结果将通过提高我们对控制神经元命运的因素的理解而具有重要的益处，并将有助于开发神经退行性疾病的治疗方法。

Signaling by the two NGF receptors, TrkA and p75, determines the survival or death of sensory neurons and of certain brain neurons involved in memory and learning. The most baffling aspect of these receptors is that in most circumstances they cooperate with each other to maximise the survival of neurons when NGF is present, but in some situations they are opposed to each other. In the latter case, NGF treatment can lead to death, rather than rescue, of neurons. In the last three years we have developed novel antisense oligonucleotides which can be used to switch off each receptor separately. These have been, and will continue to be, particularly valuable tools for our research. We have also uncovered a novel way in which the two receptors interact (via a signal transduction molecule known as SHC), which provides us with a competitive edge in this area. We have the expertise and equipment to identify and clone the missing factors that account for the paradoxical interactions between p75 and TrkA. A successful outcome from this project will have important benefits by improving our understanding of the factors controlling neuronal fate, and will help to develop treatments for neurodegenerative diseases.