Modulation of lysosomal function for the treatment of Batten disease

调节溶酶体功能治疗巴顿病

• 批准号: 9976592
• 负责人: Marco Sardiello
• 金额: --
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2020-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976592
• 关键词: AKT inhibition; Adolescent; Autophagocytosis; Basic Science; Binding; Biogenesis; Biological Assay; Brain; CLN3 gene; Carbohydrates; Cells; Cessation of life; Chemicals; Child; Childhood; Clinical Treatment; Dasatinib; Data; Defect; Dementia; Deterioration; Disease; Disease Progression; Enhancers; Enzymes; Estrogen receptor positive; Event; FDA approved; Foundations; Functional disorder; Genetic; Goals; Golgi Apparatus; Guanosine Triphosphate Phosphohydrolases; Hereditary Disease; IGF Type 2 Receptor; Impairment; Inherited; Knock-in; Lead; Lysosomes; Malignant Neoplasms; Mediating; Modeling; Monitor; Motor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Ceroid-Lipofuscinosis; Neurons; Onset of illness; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Regimen; Regulatory Pathway; Resolution; Role; Route; Sirolimus; Spielmeyer-Vogt Disease; System; Testing; Therapeutic Intervention; Tissues; Translating; Trehalose; Work; base; burden of illness; clinical development; combinatorial; dosage; experimental study; in vivo; inhibitor/antagonist; kinase inhibitor; lysosomal proteins; mannose 6 phosphate; mouse model; neuroinflammation; neuron loss; neuropathology; novel; novel therapeutics; prevent; protein kinase inhibitor; recruit; side effect; small molecule inhibitor; therapy development; trafficking

PROJECT SUMMARY/ABSTRACT Neuronal ceroid lipofuscinoses (NCLs or Batten disease) 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 undegraded cellular material; this accumulation is thought to result from defects in the autophagy-lysosomal pathway, but could itself contribute to pathogenesis. Our data show that deficiency of the juvenile Batten disease protein, CLN3, impairs maturation of a subset of lysosomal enzymes and that trehalose-mediated activation of TFEB, a master regulator of the autophagy-lysosomal pathway, ameliorates disease burden in a mouse model of juvenile Batten disease (JNCL). We propose to study novel mechanisms of TFEB activation that could lead to translational applications for JNCL and other neurodegenerative disorders caused by defects in lysosome-mediated cellular clearance. First, we will test the hypothesis that trehalose- induced lysosomal enhancement corrects defective maturation of lysosomal enzymes in JNCL mice (Aim 1). We will test this hypothesis by conducting experiments of protein maturation and by unbiased proteomic analyses based on the use of a knock-in Lamp1FLAG mouse line we have generated to efficiently isolate lysosomes from mouse tissues. Second, we will test the hypothesis that reduction or inhibition of Akt, a kinase inhibitor of TFEB we have identified, will decrease neuropathology of JNCL mice (Aim 2). We will reduce Akt activity by using two complementary approaches: genetically, by using Akt1-/- mice, and pharmacologically, by using an Akt drug inhibitor that is currently in clinical development. Third, we will test the hypothesis that synergistic pharmacological activation of TFEB by modulation of two orthogonal pathways will result in a greater enhancement of the autophagy-lysosomal system and better reduction of JNCL pathological hallmarks than either strategy alone (Aim 3). This hypothesis is based on our finding that the non-receptor tyrosine kinase, Src, is an essential factor for activation of mTORC1, another kinase inhibitor of TFEB. These studies will pioneer pharmacological activation of TFEB in a model of neurodegenerative disorder. If successful, this study will provide a powerful paradigm of TFEB activation that could lay the foundation for the clinical treatment of Batten disease and, potentially, additional neurodegenerative storage disorders caused by impairment of the autophagy-lysosomal pathway.

项目总结/文摘