Cellular Pathology of Batten Disease

Batten 病的细胞病理学

基本信息

批准号：
7275767
负责人：
Shannon L Macauley-Rambach
金额：
$ 2.78万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7275767
关键词：
A Mouse Affect Astrocytes Behavior Behavioral CLN1 gene Cell Lineage Cells Central Nervous System Diseases Childhood Chimeric Proteins Class Cognitive Cognitive deficits Data Disease Disease Progression Disruption End Point Enzymes Family Functional disorder Gene Transfer Glial Fibrillary Acidic Protein Human Impairment In Vitro Infantile neuronal ceroid lipofuscinosis Inherited Investigation LacZ Genes Lead Link Lysosomal Storage Diseases Membrane Modeling Motor Mus Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Neuronal Ceroid-Lipofuscinosis Neurons Pain Pathogenesis Pathology Patient Care Patients Personal Satisfaction Phenotype Physiological Physiology Process Proteins Purpose Role Seizures Sensory Spielmeyer-Vogt Disease Standards of Weights and Measures Testing Time Transgenic Mice Transgenic Organisms Transmembrane Domain cell type cellular pathology cerebral atrophy clinical phenotype congenic cost functional disability improved in vivo infancy motor deficit mouse model neuron loss neuropathology novel strategies prevent promoter thioesterase PPT1 gene product tool uptake

项目摘要

DESCRIPTION (provided by applicant): The purpose of this proposal is to gain a better understanding of the cellular mechanisms leading to pathological changes and functional deficits in infantile neuronal ceroid lipofuscinoses (INCL). Although the clinical phenotype is well documented in patients with INCL, little is known about how changes in the cytoarchitecture of the central nervous system (CMS) give rise to the severe cognitive, motor, physiological, and sensory deficits associated with this disease. By systematically investigating the neuronal and glial pathology and its relationship with functional changes in INCL, a greater understanding of disease pathogenesis can occur. Since INCL results from a global deficiency in the enzyme palmitoyl protein thioesterase 1 (PPT1), it remains unclear how the underlying cellular pathology in both glia or neurons leads to physiological deficits and behavioral impairment. With recent data demonstrating that astrocyte activation precedes neurodegeneration in a mouse model of INCL, we hypothesize that astrocyte dysfunction leads to functional changes in the PPT1 deficient (-/-) mice. We will test this hypothesis by selectively restoring PPT1 activity within astrocytes in PPT1-/- mice. Due to the principle of 'cross correction', traditional gene transfer and transgenic approaches cannot be employed. Therefore, we will use a lysosomal membrane- tethered form of PPT1 (PPT1-LAMP) in combination with cell specific promoters to achieve selective PPT1 expression in transgenic mice. This novel approach will provide a useful tool to investigate the cellular mechanisms contributing to pathological and functional changes in INCL. No treatment is currently available for INCL. As a class of disorders, neuronal ceroid lipofuscinoses (NCLs) represent one the most common forms of inherited pediatric neurodegenerative disorders worldwide with INCL being the most devastating form of these diseases. By gaining a greater understanding of the disease process in the CNS of patients with INCL, more efficacious and better targeted therapies can be developed for the treatment of INCL. This will not only help improve the standard of care of these patients but also help alleviate the pain, suffering, and cost of care for patient's families.

描述（由申请人提供）：本提案的目的是更好地了解导致婴儿神经元蜡样脂褐质沉积症（INCL）病理变化和功能缺陷的细胞机制。尽管 INCL 患者的临床表型已有充分记录，但人们对中枢神经系统 (CMS) 细胞结构的变化如何导致与该疾病相关的严重认知、运动、生理和感觉缺陷却知之甚少。通过系统地研究 INCL 的神经元和神经胶质病理学及其与功能变化的关系，可以更好地了解疾病的发病机制。由于 INCL 是由于棕榈酰蛋白硫酯酶 1 (PPT1) 酶整体缺乏所致，因此目前尚不清楚神经胶质细胞或神经元中的潜在细胞病理学如何导致生理缺陷和行为障碍。最近的数据表明，在 INCL 小鼠模型中，星形胶质细胞激活先于神经变性，我们推测星形胶质细胞功能障碍会导致 PPT1 缺陷 (-/-) 小鼠的功能变化。我们将通过选择性恢复 PPT1-/- 小鼠星形胶质细胞内的 PPT1 活性来检验这一假设。由于“交叉校正”原理，传统的基因转移和转基因方法无法采用。因此，我们将使用溶酶体膜束缚形式的 PPT1 (PPT1-LAMP) 与细胞特异性启动子相结合，以在转基因小鼠中实现选择性 PPT1 表达。这种新方法将为研究导致 INCL 病理和功能变化的细胞机制提供有用的工具。目前尚无针对 INCL 的治疗方法。作为一类疾病，神经元蜡样脂褐质沉积症 (NCL) 代表了全球遗传性儿科神经退行性疾病最常见的形式之一，其中 INCL 是这些疾病中最具破坏性的形式。通过更好地了解 INCL 患者中枢神经系统的疾病过程，可以开发出更有效、更好的靶向疗法来治疗 INCL。这不仅有助于提高这些患者的护理水平，而且有助于减轻患者家属的痛苦和护理费用。