Cellular Pathology of Batten Disease

描述(申请人提供)：这项建议的目的是为了更好地了解导致婴儿神经元蜡样脂褐素增多症(INCL)病理变化和功能缺陷的细胞机制。虽然临床表型在INCL患者中有很好的文献记载，但关于中枢神经系统(CMS)细胞结构的变化如何导致与这种疾病相关的严重的认知、运动、生理和感觉障碍，我们知之甚少。通过系统研究INCL中神经元和神经胶质细胞的病理变化及其与功能改变的关系，可以更好地了解疾病的发病机制。由于INCL是由棕榈酰基蛋白硫酯酶1(PPT1)的全局性缺失引起的，目前还不清楚胶质细胞或神经元的潜在细胞病理如何导致生理缺陷和行为障碍。根据最近的数据显示，在INCL小鼠模型中，星形胶质细胞的激活先于神经退行性变，我们假设星形胶质细胞功能障碍导致PPT1缺陷(-/-)小鼠的功能变化。我们将通过选择性地恢复PPT1-/-小鼠星形胶质细胞中的PPT1活性来检验这一假设。由于“交叉纠正”的原则，传统的基因转移和转基因方法不能使用。因此，我们将使用溶酶体膜连接形式的PPT1(PPT1-LAMP)与细胞特异性启动子相结合，在转基因小鼠中实现PPT1的选择性表达。这一新的方法将为研究INCL病理和功能改变的细胞机制提供有用的工具。目前还没有针对INCLL的治疗方法。神经元型蜡样脂褐素沉积症(NCLS)是世界范围内最常见的遗传性儿童神经退行性疾病之一，其中INCLL是最具破坏性的一种。通过更好地了解INCL患者中枢神经系统的疾病过程，可以开发出更有效和更好的靶向性治疗方法。这不仅有助于提高这些患者的护理水平，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.