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）：溶酶体疾病如IV型粘脂沉积症（MLIV）、Tay-Sachs和Niemann-Pick的治疗策略非常有限。与溶酶体贮积病类似，MLIV 的特点是严重的神经系统和眼科异常，通常在出生后第一年出现认知障碍和失明。它是由 MCOLN1 突变引起的，MCOLN1 是编码 mucolipin-1 (MLN1) 的基因，我们最近将其确定为由 Ca 2+ 瞬时调节的 Ca2+ 渗透性阳离子通道。它还可渗透 Na+、K+ 和其他阳离子。此外，我们的工作表明，自然发生的突变型 MLN1 通道仅被细胞内 Ca 2+ (Cai) 的增加微弱激活，并表现出其他功能异常。我们对 MLIV 患者的成纤维细胞进行了表征，发现 Ca2+ 信号减弱，并且细胞定位发生改变的大溶酶体。这些细胞中一个显着的表型改变是溶酶体胞吐作用的抑制，这是该途径的最终步骤，是 Ca 2+- 独立过程，在与伤口愈合和将货物输送到细胞外空间相关的膜重新密封中发挥作用。溶酶体胞吐作用也可能在清除细胞损伤部位附近的细胞碎片和清除细胞中的某些废物方面发挥作用。这些过程的紊乱可能与角膜混浊和胃酸缺乏以及精神运动反应改变有关，这些都是这种悲惨的儿童疾病的特征。本研究的总体目标是评估膳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溶酶体清除方面的有益作用。具体目标如下：1）检验溶酶体分解代谢酶激活剂和其他天然膳食产品可用于增加粘脂沉积症 IV 患者细胞中溶酶体清除率的假设； 2) 确定最有效的化合物的剂量反应曲线及其在具有不同MLN1突变的患者细胞中的作用时程； 3) 检验以下假设：某些药物可引发协同效应，并对来自患有其他溶酶体贮积症（例如 Tay-Sachs 和 Niemann-Pick）患者的细胞产生有益作用。从长远来看，最有效的药物组合可以用作补充/替代药物，以减少这些主要影响新生儿和青少年儿童的破坏性疾病中溶酶体过程的损害。