A Drosophila model of Batten Disease

描述(申请人提供)：这项研究的长期目标是发展果蝇作为研究婴儿神经元蜡样脂褐素沉着症(INCL)病因学的模型系统。INCL是一组相关的神经系统疾病之一，统称为巴顿病，主要影响婴儿和儿童。像所有形式的巴顿病一样，INCL是一种致命的神经退行性疾病，其特征是细胞学证据显示溶酶体功能异常。INCL是由棕榈酰蛋白硫酯酶基因(PPT1)突变引起的，但其神经发病的分子机制尚不清楚。研究INCL的新方法将有助于加速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表明，果蝇含有许多与人类疾病基因同源的基因，包括PPT1。如果果蝇PPT1的突变(DmPPT1)能够概括人类INCL的某些方面，它将提供一个在模型系统中研究INCL病因的机会，在这个模型系统中，可以利用广泛的遗传和分子工具进行研究。本申请中提出的实验的目的是确定果蝇中DmPPT1的突变是否导致人类INCLI的神经表型特征。该提案的具体目的是：1.确定通过基因突变去除DmPPT1功能的表型后果。2.确定RNAi干扰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.