A Drosophila model of Batten Disease

描述（由申请人提供）：本研究的长期目标是开发果蝇作为研究婴儿神经元蜡样质脂褐质沉积症（INCL）病因学的模型系统。INCL是一组相关的神经系统疾病之一，统称为Batten病，主要影响婴儿和儿童。与所有形式的Batten病一样，INCL是一种致命的神经退行性疾病，其特征在于溶酶体功能异常的细胞学证据。INCL是由棕榈酰蛋白硫酯酶基因（PPT 1）突变引起的，但神经元发病机制的分子机制尚不清楚。INCL研究的新方法将有助于加快发现这种毁灭性疾病的治疗方法。最近对果蝇基因组的测序显示，果蝇携带许多人类疾病基因的同源物，包括PPT 1。如果果蝇PPT1（DmPPT1）的突变是重演人类INCL的方面，它将提供一个机会，在一个模型系统中，广泛的遗传和分子工具可用于调查INCL的病因。本申请中提出的实验的目的是确定果蝇中DmPPT1的突变是否引起人INCL的神经学表型特征。该提案的具体目标是：1。确定通过基因突变去除DmPPT1功能的表型后果。2.确定通过RNA干扰破坏DmPPT1功能的表型后果。

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop Drosophila as a model system for studying the etiology of infantile neuronal ceroid lipofuscinosis (INCL). INCL is one of a group of related neurological diseases collectively known as Batten Disease that primarily affect infants and children. INCL, like all forms of Batten Disease, is a fatal neurodegenerative disease characterized by cytological evidence of abnormal lysosome function. INCL is caused by mutations in the palmitoyl-protein thioesterase gene (PPT1), but the molecular mechanism of neuronal pathogenesis is not known. Novel approaches to the study of INCL will help expedite the discovery of treatments for this devastating disease. The recent sequencing of the Drosophila genome has revealed that flies harbor many homologs of human disease genes, including PPT1. If mutation of Drosophila PPT1 (DmPPT1) were to recapitulate aspects of human INCL, it would provide an opportunity to investigate the etiology of INCL in a model system where extensive genetic and molecular tools are available for investigation. The goal of experiments proposed in this application is to determine if mutation to DmPPT1 in Drosophila causes neurological phenotypes characteristic of human INCL. The specific aims of the proposal are: 1. Determine the phenotypic consequences of removing DmPPT1 function by gene mutation. 2. Determine the phenotypic consequences of disrupting DmPPT1 function by RNA interference.