IDENTIFICATION OF AXONAL DEGENERATION PATHWAYS

描述(申请人提供)：神经性疾病给患者和家庭带来了巨大的个人负担，给社会带来了经济负担。随着我们人口的迅速老龄化，这些负担估计在未来几十年内将急剧增加。传统的研究工作侧重于确定不同的病因，并针对阿尔茨海默病、中风、多发性硬化症、青光眼和周围神经病等衰弱的神经疾病开发针对疾病的治疗方法。作为另一种选择，我们正在关注这些疾病的一个共同特征--受损轴突的退化。我们假设，一条常见的、进化上保守的细胞生物学途径会触发轴突退化，抑制这一途径将保留轴突连接，并作为这些和其他神经系统疾病的有效治疗方法。为了验证这一假设，我们正在开发一套创新的、高通量的工具，用于使用果蝇和初级小鼠神经系统在全基因组范围内识别和表征参与轴突降解的蛋白质和途径。通过专注于在两个系统中都得到验证的候选人，我们预计将阐明这一关键计划。我们将鉴定一系列蛋白质，其中一些 可能代表合理的药理靶点，可以被调节以阻断或延缓轴突变性。如果成功，这项提议将刺激开发一系列破坏性神经疾病的治疗方法。

DESCRIPTION (provided by applicant): Neurological disease represents a tremendous personal burden to patients and families and financial burden to society. With our rapidly aging population, these burdens are estimated to increase dramatically in the coming decades. Conventional research efforts focus on identifying the distinct etiologies and developing disease-specific treatments for debilitating neurological disorders such as Alzheimer's Disease, stroke, Multiple Sclerosis, glaucoma, and peripheral neuropathy. As an alternative, we are focusing on a shared feature of these disorders-the degeneration of injured axons. We hypothesize that a common, evolutionarily conserved cell biological pathway triggers axonal degeneration, and that inhibiting this pathway will preserve axonal connections and serve as an effective treatment in these and other neurological diseases. To test this hypothesis, we are developing an innovative, high-throughput set of tools for the genome-wide identification and characterization of proteins and pathways involved in axonal degradation using both Drosophila and primary mouse neuronal systems. By focusing on candidates validated in both systems, we anticipate elucidating this critical program. We will identifying a host of proteins, some of which are likely to represent reasonable pharmacological targets that could be modulated in order to block or delay axonal degeneration. If successful, this proposal will stimulate the development of treatments for a wide range of devastating neurological disorders.