Effects of dietary agents on lysosomes in mucolipidosis

膳食制剂对粘脂沉积症溶酶体的影响

• 批准号: 6946905
• 负责人: PETER M VASSILEV
• 金额: $ 21.26万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6946905
• 关键词: Tay Sachs disease; Xenopus; alternative medicine; biological products; biological signal transduction; biotherapeutic agent; calcium ion; diet therapy; dietary supplements; dosage; electrophysiology; exocytosis; gene mutation; inborn lysosomal enzyme disorder; lysosomes; microscopy; mucopolysaccharidosis type I; nutrition related tag

DESCRIPTION (provided by applicant): The therapeutic strategies for lysosomal diseases such as mucolipidosis type IV (MLIV), Tay-Sachs and Niemann-Pick are very limited. Similar to the lysosomal storage diseases, MLIV is characterized by severe neurologic and ophthalmologic abnormalities and usually presents during the first year of life with cognitive impairment and blindness. It is caused by mutations in MCOLN1, the gene encoding mucolipin-1 (MLN1), which we have recently established to be a Ca2+-permeable cation channel that is transiently modulated by Ca 2+. It is also permeable to Na +, K+, and other cations. In addition, our work has shown that naturally occurring mutant MLN1 channels are only weakly activated by increases in intracellular Ca 2+ (Cai) and show other functional abnormalities. We have characterized fibroblasts from MLIV patients and found diminished Ca2+ signaling and large lysosomes with altered cellular localization. A significant phenotypic alteration in these cells is the inhibition of lysosomal exocytosis, the terminal step in the pathway, which is a Ca 2+- independent process that plays a role in membrane resealing related to wound healing and delivery of cargo to the extracellular space. Lysosomal exocytosis is also likely to function in the removal of cellular debris near sites of cellular damage and in removal of certain waste products from the cell. It is possible that a disturbance in these processes could be implicated in corneal opacification and achlorhydria, and altered psychomotor response, all hallmarks of this tragic childhood disease. The overall goal of this study is to assess the beneficial effects of dietary compounds and related natural products in promoting lysosomal clearance in cells of MLIV and other lysosomal disorders. The specific aims are as follows: 1) test the hypothesis that activators of lysosomal catabolic enzymes and other natural dietary products can be used to increase lysosomal clearance from cells of patients with mucolipidosis IV; 2) to determine the dose-response curves of the most effective compounds and the time-course of their actions in cells from patients with different mutations of MLN1; and 3) test the hypothesis that some agents elicit synergistic effects and exert beneficial actions on cells derived from patients with other lysosomal storage disorders such as Tay-Sachs and Niemann-Pick. In the long term, the most effective drug combination may be employed as a complementary/alternative medicine for reducing the damage of the lysosomal processes in these devastating diseases affecting mainly children of neonatal and adolescent ages.

描述（由申请人提供）：溶酶体疾病的治疗策略，例如IV型（MLIV），TAY-SACHS和NIEMANN-PICK非常有限。与溶酶体储存疾病相似，MLIV的特征是严重的神经系统和眼科异常，通常在生命的第一年中出现认知障碍和失明。它是由McOLN1（编码粘脂蛋白-1（MLN1）的基因）中的突变引起的，我们最近确定为Ca2+可渗透阳离子通道，该通道由Ca 2+暂时调节。 Na +，K +和其他阳离子也可以渗透。此外，我们的工作表明，天然存在的突变体MLN1通道仅通过细胞内Ca 2+（CAI）的增加而被薄弱地激活，并显示其他功能异常。我们已经表征了来自MLIV患者的成纤维细胞，发现CA2+信号传导减少，大溶酶体随细胞定位的改变。这些细胞中的显着表型改变是抑制溶酶体胞吐作用，这是途径中的末端步骤，即Ca 2+ - 独立的过程在与货物的伤口愈合和递送到细胞外空间有关的膜上起作用。溶酶体胞吐作用也可能在细胞损伤部位附近的细胞碎片以及从细胞中去除某些废物产物中的作用。这些过程中的干扰可能与角膜不透明和achlorhydria有关，并改变了精神运动反应，这是这种悲惨的儿童疾病的所有标志。这项研究的总体目的是评估饮食化合物和相关天然产物在促进MLIV和其他溶酶体疾病细胞中溶酶体清除率方面的有益作用。具体目的如下：1）检验以下假设：溶酶体分解代谢酶和其他天然饮食产物的活化剂可用于增加粘膜脂肪性病IV患者细胞的溶酶体清除率； 2）确定最有效化合物的剂量反应曲线及其在具有不同MLN1突变患者的细胞中作用的时间顺序； 3）检验以下假设：某些药物会引起与其他溶酶体储存障碍患者（如Tay-Sachs和Niemann-pick）衍生出的细胞的协同作用并发挥有益的作用。从长远来看，最有效的药物组合可以用作互补/替代药物，以减少这些毁灭性疾病的溶酶体过程损害，主要影响新生儿和青少年时代的儿童。