Proteolytic cleavage of the p75 neurotrophin receptor mediates cell death

p75色氨酸受体（p75NTR）是神经细胞死亡的主要诱导物，并且在广泛的神经变性病症中是活性的，包括阿尔茨海默病、运动神经元病、多发性硬化、中风和神经创伤。本研究的目的是了解和验证调节这种受体的事件。特别是，我们将调查的作用，裂解或控制的受体在介导其细胞死亡活动中发挥的作用。这个建议的一个基本方面是确定是否裂解是由于早老素依赖性活动，早老素突变已被证明在大多数家族性阿尔茨海默病病例。虽然这将增加我们对导致阿尔茨海默病的因素之一的理解，但它也具有更广泛的影响。已经开发了多种调节早老素裂解的药物，并对其在治疗阿尔茨海默病中的功效进行了临床测试。如果我们的研究证明p75NTR裂解是调节神经元变性的关键过程，那么它将对其他p75NTR相关神经变性疾病的治疗方法产生重大影响。

The p75 neutrotophin receptor (p75NTR) is a major inducer of nerve cell death, and is active in a wide range of neurodegenerative conditions, including Alzheimer's disease, motor neuron disease, multiple sclerosis, stroke and nerve trauma. This study aims to understand and to characterise the events that regulate this receptor. In particular, we will investigate the role that cleavage or controlled breakdown of the receptor plays in mediating its cell death activity. A fundamental aspect of this proposal is determining whether cleavage is due to presenilin-dependent activity, given that presenilin mutations have been demonstrated in most familial Alzheimer s disease cases. While this will increase our understanding of one of factors contributing to Alzheimer's disease, it also has much broader implications. A wide range of pharmaceuticals which regulate presenilin cleavage are already being developed and clinically tested for their efficacy in the treatment of Alzheimer s disease. Should our research demonstrate that p75NTR cleavage is the key process that regulates neuronal degeneration it will have major ramifications for approaches to the treatment of other p75NTR-associated neurodegenerative conditions.