IDENTIFICATION OF AXONAL DEGENERATION PATHWAYS

描述（由申请人提供）：神经系统疾病对患者和家庭造成巨大的个人负担，对社会造成经济负担。随着我们人口的迅速老龄化，这些负担估计将在未来几十年急剧增加。传统的研究工作集中在确定不同的病因和开发用于衰弱性神经障碍的疾病特异性治疗，例如阿尔茨海默病、中风、多发性硬化症、青光眼和周围神经病。作为替代方案，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，一个共同的，进化上保守的细胞生物学途径触发轴突变性，抑制这一途径将保留轴突连接，并作为一种有效的治疗这些和其他神经系统疾病。为了验证这一假设，我们正在开发一套创新的高通量工具，用于全基因组识别和表征使用果蝇和原代小鼠神经元系统参与轴突降解的蛋白质和途径。通过关注在这两个系统中验证的候选人，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学靶点，可以调节这些靶点以阻断或延迟轴突变性。如果成功的话，这一提议将刺激广泛的破坏性神经系统疾病的治疗方法的发展。

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.