Influence of lipid raft dynamics on PKC-mediated protective signaling in neurons.

描述(由申请人提供)：本申请的长期目标是了解Krabbe病发病的重要潜在机制。Krabbe病是一种破坏性的遗传性儿童鞘脂沉积症，其进展的特点是脂质精神质的积聚。不幸的是，使用酶替代方法治疗这种疾病的进展有限。人们认为，治疗仅取得有限成功的原因之一是，在酶替代能够发挥作用之前，神经系统已经受到了太多的损害。考虑到这一点，研究早期疾病机制的重要性就变得非常明显。例如，脱髓鞘通常被认为是Krabbe病造成的主要侮辱，但它可能只是这种疾病改变中枢神经系统的众多机制之一。正如最近所描述的，神经元似乎容易受到疾病过程的影响，无论它们是否与髓鞘细胞或髓鞘细胞有重大接触。这表明，早期保护神经细胞群体的药物干预可能对治疗这些患者有一定的好处。这项研究的具体目的就是为了解决这种可能性。为了实现这些目标，本应用程序建议使用Krabbe病小鼠模型的原代神经元培养来研究对神经元生存至关重要的信号机制是否在疾病进展过程中受到影响。具体地说，我们最近接受的手稿强调，精神病可以通过改变细胞膜内称为脂筏的信号平台来干扰信号传递。这种疾病进展的机制将在神经元中进行研究，以确定它是否可能导致神经保护信号的丢失，而神经保护信号对这些细胞在疾病期间的维持至关重要。此外，这项建议建议使用替代药理学方法来诱导神经保护信号，这将有助于描述这些药物与酶替代是否可以提供更有效的治疗，从而为患有克拉贝病的儿童提供更好的结果。对于公众：Krabbe病是一种破坏性和致命性的神经系统疾病，影响着世界各地的许多儿童。该项目旨在为对目前治疗这种疾病的方法进行重大改变提供基础，并旨在改善这些患者的生活时间和质量。

DESCRIPTION (provided by applicant): This application is presented with the long term objective of understanding important underlying mechanisms for the pathogenesis of Krabbe disease. Krabbe disease is a devastating genetic pediatric sphingolipidosis whose progression is characterized by the accumulation of the lipid psychosine. Unfortunately, only limited progress has been made using enzyme replacement methods for the treatment of this disease. It is thought that one of the reasons that treatment has been met with only limited success is that too much damage has been done to the nervous system before enzyme replacement is able to exert an effect. With this in mind, the importance of studying early disease mechanisms becomes quite clear. For example, demyelination, which is commonly thought to be the major insult that results from Krabbe disease, may be only one of many mechanisms by which the disease alters the central nervous system. As has been described recently, neurons appear to be susceptible to disease processes independently of whether or not they have had significant contact with myelin or myelinating cells. This suggests that pharmacological interventions to protect neuronal cell populations early on may be of some benefit in treating these patients. The specific aims of this study are designed to address this possibility. In order to achieve these goals, this application proposes to use primary neuronal culture from a Krabbe disease mouse model to investigate whether signaling mechanisms important to neuron survival are compromised during disease progression. Specifically, our recently accepted manuscript has highlighted that psychosine can interfere with signaling by altering signaling platforms known as lipid rafts within the cell membrane. This mechanism for disease progression will be looked at in neurons to see whether it may drive the loss of neuorprotective signals that would be important for the maintenance of these cells during disease. In addition, this proposal suggests the use of alternative pharmacological methods for the induction of neuroprotective signaling which will help to describe whether these drugs in combination with enzyme replacement may provide a more effective treatment and thus a better outcome for children suffering from Krabbe disease. FOR THE PUBLIC: Krabbe disease is a devastating and lethal disorder of the nervous system that affects many children throughout the world. This project is designed to provide a basis for significant alterations in the current approach for the treatment of this disease and is aimed at improving the length and quality of life of these patients.