BATTEN DISEASE, MEMBRANE LIPIDS AND SIGNAL TRANSDUCTION

这项研究的长期目标是阐明主要的 生物化学和分子缺陷导致幼年神经元 蜡样脂褐质沉积症（JNCL，Batten病，Spielmeyer-Vogt-Sjogren 疾病）。 NCL是一组严重的不可治疗的遗传性神经退行性疾病， 基本缺陷仍然未知的疾病。 原本 被归类为一组常见的疾病，最近的分子研究 表现出异质性。 该项目将重点研究一个 JNCL患者的同质队列，通过以下连锁研究定义： 我们已经记录了16号染色体上的一个严重的 循环红细胞和血小板膜缺陷 磷脂 我们已经开发了一种模型，基于培养的皮肤成纤维细胞来研究 膜磷脂和磷脂依赖性膜功能。 我们 将提供初步数据，并概述进一步的实验，以证实 培养的细胞表达了疾病的过程， 储存物质的积累和膜磷脂缺乏。 我们建议使用该模型来研究体外 多不饱和脂肪酸（PUFA）的干扰，因为有 越来越多的体内证据表明，PUFA补充剂 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测重要的磷脂依赖性膜 特别是关于信号转导的功能， 蛋白激酶C（PKC）基因的活性和基因表达 家庭 PKC是一种重要的信号调节酶 转导 这些都是高度依赖，并可能调节，正常 膜磷脂重塑过程。 我们将提出初步的 证明PKC膜失效的证据和研究策略 易位在我们的JNCL成纤维细胞系，并提出， PKC的缺陷可能是JNCL的主要缺陷。 我们还将提出一种策略，以评估PKC基因家族居住在 16号染色体（与JNCL基因连锁的区域内），并测试 假设影响新PKC同工酶的突变是候选者， JNCL基因。 了解JNCL的生化和分子原因将使我们能够 制定新的诊断和治疗策略。 这些研究将 提供有关功能的更多基本信息， PKC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.