Chemical modulation of lysosomal storage in vivo

描述（由申请人提供）：溶酶体贮积病是一组多系统疾病，其共同病理特征是溶酶体中储存物质的异常积累。溶酶体贮积病常影响中枢神经系统并引起显著的神经系统疾病。中枢神经系统的表现尤其难以用现有的治疗方法治疗。我们建议在这里直接筛选中枢神经系统渗透分子，减少异常溶酶体储存。我们之前对缺乏溶酶体酶组织蛋白酶D的果蝇进行了表征，并表明它们代表了由患者、羊和鼠模型中组织蛋白酶D基因突变引起的神经元类脂褐质病异常溶酶体储存特征的可靠模型。我们现在建议在我们的模型中进行体内药物筛选，以确定可以减少或消除异常溶酶体储存物质的小分子。从我们的筛选中出现的分子不仅能够以一种促进储存物质清除的方式调节溶酶体的功能，而且还具有穿透体内功能血脑屏障的能力。因此，这些药物将代表有吸引力的候选治疗药物在神经元脂褐蛋白病，以及可能的其他溶酶体贮积性疾病。这些分子也可能为探讨溶酶体在正常和异常生理条件下的功能提供有用的研究工具。最后，鉴于新的证据表明自噬体/溶酶体系统在其他神经退行性疾病中发生改变，包括阿尔茨海默病，我们鉴定的分子也可能与更常见的神经退行性疾病具有治疗相关性。公共卫生相关性：溶酶体贮积病是一种破坏性疾病，可导致受影响儿童严重残疾和早期死亡。我们将使用一种快速、廉价的体内模型系统来识别减少溶酶体储存的化合物，这些化合物被认为会导致这些疾病中的神经元死亡和功能障碍。我们系统的结果将提供重要的候选治疗方法，也可能帮助我们了解异常神经元储存如何导致细胞死亡。

DESCRIPTION (provided by applicant): Lysosomal storage diseases are a group of multisystem disorders characterized by the common pathology of abnormal accumulation of storage material in lysosomes. Lysosomal storage diseases often affect the central nervous system and cause significant neurological morbidity. Central nervous system manifestations have been particularly difficult to treat with currently available therapies. We propose here to screen directly for central nervous system-penetrant molecules that reduce abnormal lysosomal storage. We have previously characterized Drosophila lacking the lysosomal enzyme cathepsin D and have shown that they represent a robust model of the abnormal lysosomal storage characteristic of neuronal ceroid lipofuscinosis cause by mutations in the cathepsin D gene in patients and in ovine and murine models. We now propose carrying out an in vivo drug screen in our model to identify small molecules that can reduce or eliminate abnormal lysosomal storage material. Molecules emerging from our screen will not only have the ability to modulate lysosomal function in a fashion that promotes clearance of stored material, but will also have the ability to penetrate a functioning in vivo blood brain barrier. Thus, these drugs will represent attractive therapeutic drug candidates in neuronal lipofuscinoses, and possibly other lysosomal storage diseases as well. These molecules may also provide useful research tools to probe lysosomal function in normal and abnormal physiological conditions. Finally, given the emerging evidence that the autophagosomal/lysosomal system is altered in other neurodegenerative diseases, including Alzheimer's disease, the molecules we identify may also have therapeutic relevance to more common neurodegenerative disorders as well. PUBLIC HEALTH RELEVANCE: Lysosomal storage diseases are devastating disorders that cause severe disability and early death in affected children. We will use a fast, cheap in vivo model system to identify compounds that reduce the lysosomal storage thought to result in death of neuronal death and dysfunction in these diseases. Results from our system will provide important candidate therapeutics and may also help us understand how abnormal neuronal storage leads to cell death.