BATTEN DISEASE, MEMBRANE LIPIDS AND SIGNAL TRANSDUCTION

这项研究的长期目标是阐明 导致幼年神经细胞的生化和分子缺陷 Ceroid-Lipofuscinsis(JNCL，Batten病，Spielmeyer-Vogt-Sjogren 疾病)。 NCL是一组严重的无法治疗的遗传性神经退行性疾病 基本缺陷尚不清楚的疾病。原来是这样的 被归类为一组常见的疾病，最近的分子研究 表现出异质性。这个项目将集中研究一个 JNCL患者的同质性队列，由以下连锁研究确定 在16号染色体上，我们记录了一种严重的 循环红细胞膜和血小板膜缺陷 磷脂。 我们已经开发了一种基于培养的皮肤成纤维细胞的模型来研究 膜磷脂及其依赖的膜功能。我们 将提供初步数据并概述进一步的实验以证实 培养的细胞表现出疾病过程中的异常 贮藏物质的积累和膜磷脂的缺乏。 我们建议使用这一模型来研究体外实验的效果。 对多不饱和脂肪酸(PUFA)的扰动 越来越多的体内证据表明，补充多不饱和脂肪酸是 临床上有益于JNCL及其动物模型犬NCL。 我们将使用我们的模型来探索重要的磷脂依赖膜 特别涉及信号转导的功能和 蛋白激酶C(PKC)基因的活性和遗传表达 家人。PKC是信号调节中的重要酶类 转导。它们高度依赖于正常，并可能调节正常 膜磷脂重塑过程。我们将为您呈现初步的 证明PKC膜失效的证据和研究策略 在我们的JNCL成纤维细胞系中的易位，并提出一种 PKC缺陷可能是JNCL的主要缺陷。 我们还将提出一种策略来评估驻留在 16号染色体(在与JNCL基因连锁的区域内)，并测试 假设一个影响新的PKC同工酶的突变是候选的 JNCL的基因。 对JNCL的生化和分子病因的了解将使我们能够 制定新的诊断和治疗策略。这些研究将 提供有关功能和功能的更多基本信息 蛋白激酶C和膜磷脂的代谢。

The long-term objective of this research is to elucidate the primary biochemical and molecular defect that results in Juvenile Neuronal Ceroid-Lipofuscinosis (JNCL, Batten disease, Spielmeyer-Vogt-Sjogren disease). The NCL's are a group of severe untreatable inherited neurodegenerative diseases for which the basic defects remain unknown. Originally classified as a common group of disorders, recent molecular studies have demonstrated heterogeneity. This project will focus studies upon a homogeneous cohort of patients with JNCL, defined by linkage studies of the disease to chromosome 16, in whom we have documented a severe deficiency of circulating erythrocyte and platelet membrane phospholipids. We have developed a model, based upon cultured skin fibroblasts to study membrane phospholipids and phospholipid-dependant membrane functions. We will present preliminary data and outline further experiments to confirm that cultured cells express the disease process both in terms of abnormal accumulation of storage material and membrane phospholipid deficiency. We propose to use this model to study the effects of in vitro perturbations with polyunsaturated fatty acids (PUFA's) as there is growing in vivo evidence to suggest that PUFA supplementation is clinically beneficial in JNCL and its animal, model canine NCL. We will use our model to probe important phospholipid-dependant membrane functions with particular reference to signal transduction and the activities and genetic expression of the protein kinase C (PKC) gene families. The PKC's are an important enzymes in the regulation of signal transduction. These are highly dependant upon, and may regulate, normal membrane phospholipid remodeling processes. We will present preliminary evidence and a research strategy to demonstrate a failure of PKC membrane translocation in our JNCL fibroblast cell lines, and propose that a defect in PKC may be the primary defect in JNCL. We will also present a strategy to evaluate a PKC gene family residing on chromosome 16 (within the region linked to the JNCL gene) and to test the hypothesis that a mutation affecting a novel PKC isozyme is a candidate gene for JNCL. Knowledge of the biochemical and molecular cause of JNCL will allow us to develop new strategies for diagnosis and treatment. The studies will provide more fundamental information regarding the function and metabolism of PKC and membrane phospholipids.