Chemical modulation of lysosomal storage in vivo

描述(申请人提供)：溶酶体储藏疾病是一组以溶酶体内储藏物质异常堆积为特征的常见病理变化为特征的多系统疾病。溶酶体储存性疾病通常影响中枢神经系统，并导致显著的神经系统疾病。目前可用的治疗方法尤其难以治疗中枢神经系统的症状。我们建议在这里直接筛选中枢神经系统穿透性分子，以减少异常溶酶体的存储。我们以前已经描述了缺乏溶酶体酶组织蛋白酶D的果蝇，并表明它们代表了由组织蛋白酶D基因突变引起的患者以及绵羊和小鼠模型中神经油样脂褐素沉积症的溶酶体异常储存特征的稳健模型。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存储物质的小分子。从我们的屏幕上涌出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，还将具有穿透体内正常运作的血脑屏障的能力。因此，这些药物将是治疗神经元性脂褐素沉着症和其他溶酶体储存性疾病的有吸引力的候选药物。这些分子也可能为探索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，鉴于新出现的证据表明，自噬/溶酶体系统在包括阿尔茨海默病在内的其他神经退行性疾病中发生了改变，我们识别的分子可能也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：溶酶体储存疾病是一种破坏性疾病，会导致受影响儿童的严重残疾和过早死亡。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存储的化合物，这些化合物被认为会导致这些疾病中神经元死亡和功能障碍的死亡。我们系统的结果将提供重要的候选治疗方法，并可能帮助我们了解异常神经元存储是如何导致细胞死亡的。

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.