Cellular Pathology of Batten Disease

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。虽然INCL患者的临床表型有充分的记录，但关于中枢神经系统（CMS）细胞结构的变化如何引起与这种疾病相关的严重认知、运动、生理和感觉缺陷，我们知之甚少。通过系统研究神经元和神经胶质病理学及其与INCL功能变化的关系，可以更好地了解疾病的发病机制。由于INCL是由棕榈酰蛋白硫酯酶1（PPT 1）的全面缺乏引起的，因此仍不清楚神经胶质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，星形胶质细胞激活之前，神经退行性病变的小鼠模型的INCL，我们假设，星形胶质细胞功能障碍导致功能的变化，在PPT 1缺陷（-/-）小鼠。我们将通过选择性恢复PPT 1-/-小鼠星形胶质细胞内的PPT 1活性来验证这一假设。由于“交叉校正”的原理，传统的基因转移和转基因方法不能使用。因此，我们将使用与细胞特异性启动子组合的PPT 1的溶酶体膜栓系形式（PPT 1-LAMP）来实现转基因小鼠中的选择性PPT 1表达。这种新的方法将提供一个有用的工具，研究细胞机制，有助于病理和功能的变化，在INCL。目前没有治疗INCL的方法。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的最常见形式之一，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CNS中的疾病过程，可以开发更有效和更好的靶向治疗INCL。这不仅有助于提高这些患者的护理标准，还有助于减轻患者家属的痛苦和护理费用。

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.