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来说是巨大的个人负担，对社会来说是巨大的经济负担。随着人口的迅速老龄化，这些负担预计在未来几十年将急剧增加。传统的研究工作集中在识别不同的病因和开发疾病特异性治疗衰弱性神经系统疾病，如阿尔茨海默病、中风、多发性硬化症、青光眼和周围神经病变。作为另一种选择，我们关注的是这些疾病的共同特征——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，抑制这一途径将保持轴突连接，并作为这些和其他神经系统疾病的有效治疗。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，用于全基因组鉴定和表征涉及果蝇和原代小鼠神经系统轴突降解的蛋白质和途径。通过关注在两个系统中验证的候选人，我们期望阐明这一关键程序。我们将鉴定一系列蛋白质，其中一些

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. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will identify potential therapeutic targets for a host of debilitating neurological disorders. Axonal degeneration is a shared component of many neurological disorders including neurodegenerative diseases like Alzheimer's, Parkinson's and Multiple Sclerosis, and it is also an important aspect of hereditary, chemotherapy-induced and diabetic neuropathies, stroke, and glaucoma. Defining the molecular mechanisms of the axonal self-destructive pathway will identify novel therapeutic candidates for these disorders where morbidity is largely caused by axonal dysfunction.