权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目概要/摘要神经元蜡样脂褐质沉积症（NCL 或 Batten 病）是最具破坏性的遗传性疾病之一童年时期的疾病，也是美国儿童神经退行性变的最常见原因。目前还没有治愈这些疾病，并且治疗在很大程度上仍然是支持性的。 NCL 的特点是进行性未降解的细胞物质在溶酶体内积累；这种积累被认为是缺陷造成的在自噬-溶酶体途径中，但其本身可能有助于发病机制。我们的数据表明，缺乏幼年巴顿病蛋白 CLN3 会损害溶酶体酶子集的成熟海藻糖介导的 TFEB 激活（自噬溶酶体途径的主要调节因子）可改善幼年巴顿病（JNCL）小鼠模型的疾病负担。我们建议研究新机制 TFEB 激活可能导致 JNCL 和其他神经退行性疾病的转化应用由溶酶体介导的细胞清除缺陷引起。首先，我们将检验以下假设：海藻糖- 诱导的溶酶体增强可纠正 JNCL 小鼠溶酶体酶的成熟缺陷（目标 1）。我们将通过进行蛋白质成熟实验和无偏蛋白质组学实验来检验这一假设基于使用我们生成的敲入 Lamp1FLAG 小鼠品系进行分析，以有效分离来自小鼠组织的溶酶体。其次，我们将检验以下假设：Akt（一种激酶）的减少或抑制我们已经确定的 TFEB 抑制剂将减少 JNCL 小鼠的神经病理学（目标 2）。我们将减少 Akt 活性通过使用两种互补的方法：遗传上，通过使用 Akt1-/- 小鼠，以及药理学上，通过使用目前处于临床开发阶段的 Akt 药物抑制剂。第三，我们将检验以下假设：通过调节两个正交途径对 TFEB 进行协同药理学激活将导致自噬-溶酶体系统的更大增强和 JNCL 病理标志的更好减少比单独使用任一策略（目标 3）更有效。该假设基于我们的发现，即非受体酪氨酸激酶 Src 是激活 mTORC1（另一种 TFEB 激酶抑制剂）的重要因子。这些研究将在神经退行性疾病模型中开创 TFEB 的药理学激活。如果成功的话，这研究将为 TFEB 激活提供强大的范例，为临床治疗奠定基础 Batten 病，以及可能由神经功能受损引起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.