Modulation of lysosomal function for the treatment of neuronal ceroid lipofuscino

调节溶酶体功能治疗神经元蜡样脂褐质

基本信息

批准号：
8660355
负责人：
Marco Sardiello
金额：
$ 34.07万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660355
关键词：
Affect Age of Onset Animals Autophagocytosis Basic Science Behavioral Behavioral Assay Biochemical Biological Biological Availability Brain Cells Ceroid Cessation of life Chemicals Child Childhood Data Defect Dementia Deposition Deterioration Development Disaccharides Disease Disease Progression Enhancers Eukaryota Eukaryotic Cell Exocytosis Fibroblasts Foundations Genes Genetic Genetic Enhancement Genetic Transcription Glucose Goals Health Huntington Disease In Vitro Inborn Genetic Diseases Inherited Knowledge Liver Longevity Lysosomes Mammalian Cell Maps Mediating Metabolism Modeling Molecular Molecular Chaperones Molecular Genetics Motor Mus Mutate Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Ceroid-Lipofuscinosis Neurons Oculopharyngeal Muscular Dystrophy Oral Pathogenesis Pathology Pathway interactions Pharmacodynamics Phenotype Process Production Property Seizures Speed Staging Stress System Testing Therapeutic Intervention Toxic effect Transgenic Mice Transgenic Organisms Translating Trehalase Trehalose Work absorption activating transcription factor base chemical genetics disease phenotype genetic analysis human disease in vivo intestinal epithelium lipopigments metabolic abnormality assessment mouse model novel therapeutics offspring overexpression polyalanine polyglutamine protective effect small molecule therapy development trafficking transcription factor vision development

项目摘要

DESCRIPTION (provided by applicant): Neuronal ceroid lipofuscinoses (NCLs) are among the most devastating inherited disorders of childhood and the most common cause of neurodegeneration in children in the U.S. There is currently no cure for these disorders, and treatments remain largely supportive. NCLs are characterized by the progressive intralysosomal accumulation of ceroid lipopigment; this accumulation is thought to result from defects in lysosomal metabolism or trafficking, but could itself contribute to pathogenesis. We hypothesize that enhancing clearance processes will counteract disease progression in NCLs, even if the primary defect remains uncorrected. To test this hypothesis, we will boost lysosomal function by using genetic (Tfeb) and chemical (trehalose) enhancers of clearance processes in two mouse models of NCLs. In Aim 1 we will generate and characterize transgenic mice that conditionally express either a normal or constitutively active form of the transcription factor EB (TFEB), a master modulator of lysosomal and autophagic pathways. We will also perform molecular genetic analyses that will enable us to map the TFEB targetome, a crucial step in understanding its activities in health and disease. In Aim 2 we will cross these transgenics with Cln3 ex7/8 and Cln8mnd mice, two well-characterized models of NCLs, to investigate the effects of genetic TFEB enhancement on disease course. Importantly, we use models of NCL caused by mutations in two distinct genes in order to rigorously test whether TFEB- mediated clearance can indeed mitigate disease regardless of the underlying defect. In Aim 3 we will study the metabolism of trehalose, a putative inducer of autophagic pathways, which our data indicate activates TFEB; we will test the effect of trehalose on disease course in the two NCL models. Results from this project will show whether genetically or chemically induced lysosomal enhancement is able to counteract disease progression in NCLs and impact health and life span of affected animals. Positive results from this study will be the foundation for the development of a therapy for these devastating disorders. In addition, any knowledge gained from studies on NCLs could, in principle, be applicable to other neurodegenerative disorders caused by defects in lysosome-mediated cellular clearance.

描述（由申请人提供）：神经元的脂肪糖蛋白酶（NCLS）是美国儿童中最具破坏性的遗传性疾病，也是美国儿童神经退行性的最常见原因，目前无法治愈这些疾病，并且治疗方法仍然很大程度上支持。 NCLs的特征是凝胶脂质脂质胶的进行性循环体内体积累。人们认为，这种积累是由于溶酶体代谢或运输的缺陷而导致的，但本身可能导致发病机理。我们假设增强清除过程将抵消NCL的疾病进展，即使主要缺陷仍未验证。为了检验这一假设，我们将使用两种NCL小鼠模型中使用遗传（TFEB）和化学（TFEB）和化学（海藻糖）增强子来提高溶酶体功能。在AIM 1中，我们将生成和表征转录因子EB（TFEB）的正常或组成型活性形式的转基因小鼠，该形式是溶酶体和自噬途径的主调节剂。我们还将进行分子遗传分析，使我们能够映射TFEB Targetome，这是了解其在健康和疾病中的活动的关键步骤。在AIM 2中，我们将将这些转基因与CLN3 EX7/8和CLN8MND小鼠（两种良好的NCL模型）交叉，以研究遗传TFEB增强对疾病过程的影响。重要的是，我们使用由两个不同基因突变引起的NCL模型，以便严格测试TFEB介导的清除是否确实可以减轻疾病，而无论其潜在缺陷如何。在AIM 3中，我们将研究Trehalose的代谢，Tehalose是自噬途径的推定诱导剂，我们的数据表明激活TFEB。我们将在两个NCL模型中测试海藻糖对疾病课程的影响。该项目的结果将显示遗传或化学诱导的溶酶体增强是否能够抵消NCL中的疾病进展，并影响受影响动物的健康和寿命。这项研究的积极结果将是发展的基础这些毁灭性疾病的疗法。此外，原则上，从NCLS的研究中获得的任何知识都可以适用于溶酶体介导的细胞清除率缺陷引起的其他神经退行性疾病。