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Modulation of lysosomal function for the treatment of Batten disease

调节溶酶体功能治疗巴顿病

基本信息

批准号：
10247068
负责人：
Marco Sardiello
金额：
$ 34.45万
依托单位：
WASHINGTON UNIVERSITY
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247068
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 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

项目摘要

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/摘要神经元蜡样质脂褐质病（NCL或Batten病）是最具破坏性的遗传性疾病之一在美国，儿童神经退行性疾病的最常见原因。治疗这些疾病，治疗仍然在很大程度上支持。NCL的特点是渐进的未降解的细胞物质在溶酶体内的积累;这种积累被认为是由缺陷引起的自噬-溶酶体途径，但本身可能有助于发病机制。我们的数据显示，幼年巴滕病蛋白CLN 3的表达损害了溶酶体酶亚群的成熟，海藻糖介导的TFEB激活，自噬-溶酶体途径的主要调节剂，改善在幼年巴滕病（JNCL）小鼠模型中的疾病负担。我们建议研究新的机制 TFEB激活可能导致JNCL和其他神经退行性疾病的翻译应用由溶酶体介导的细胞清除缺陷引起。首先，我们将检验海藻糖- 诱导的溶酶体增强纠正了JNCL小鼠中溶酶体酶的成熟缺陷（Aim 1）。我们将通过进行蛋白质成熟实验和无偏蛋白质组学方法来验证这一假设。基于使用敲入Lamp 1FLAG小鼠系的分析，我们已经产生了有效分离来自小鼠组织的溶酶体。第二，我们将检验Akt激酶的减少或抑制我们已经鉴定的TFEB的抑制剂将减轻JNCL小鼠的神经病理学（目的2）。我们将减少Akt 活性通过使用两种互补的方法：遗传学，通过使用Akt 1-/-小鼠，和ESTA，通过使用目前正在临床开发中的Akt药物抑制剂。第三，我们将检验假设，通过调节两个正交途径协同药理学激活TFEB将导致自噬-溶酶体系统的更大增强和JNCL病理标志的更好减少而不是单独使用任何一种策略（目标3）。这一假设是基于我们的发现，非受体酪氨酸激酶Src是激活TFEB的另一种激酶抑制剂mTORC 1的必需因子。这些研究将开创TFEB在神经退行性疾病模型中的药理学激活。如果成功，这本研究将为TFEB激活提供一个强有力的范例，为临床治疗奠定基础 Batten病，以及潜在的其他神经退行性储存障碍，自噬-溶酶体途径

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lysosome biogenesis in health and disease.

DOI：
10.1111/jnc.14564
发表时间：
2019-03
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Bajaj L;Lotfi P;Pal R;Ronza AD;Sharma J;Sardiello M
通讯作者：
Sardiello M

Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction.

MTORC1 依赖性 JNK 激活减少是与溶酶体功能障碍相关的神经发育缺陷的基础。

DOI：
10.1016/j.celrep.2015.08.047
发表时间：
2015
期刊：
Cell reports
影响因子：
8.8
作者：
Wong,Ching-On;Palmieri,Michela;Li,Jiaxing;Akhmedov,Dmitry;Chao,Yufang;Broadhead,GeoffreyT;Zhu,MichaelX;Berdeaux,Rebecca;Collins,CatherineA;Sardiello,Marco;Venkatachalam,Kartik
通讯作者：
Venkatachalam,Kartik

CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis.

DOI：
10.1038/s41556-018-0228-7
发表时间：
2018-12
期刊：
Nature cell biology
影响因子：
21.3
作者：
di Ronza A;Bajaj L;Sharma J;Sanagasetti D;Lotfi P;Adamski CJ;Collette J;Palmieri M;Amawi A;Popp L;Chang KT;Meschini MC;Leung HE;Segatori L;Simonati A;Sifers RN;Santorelli FM;Sardiello M
通讯作者：
Sardiello M

A rapid and sensitive method for measuring N-acetylglucosaminidase activity in cultured cells.