Discovery of Novel Drugs for Alzheimer's Disease,

描述（由申请人提供）：该项目的目的是开发一种基因转移程序来修复或替代认知障碍个体的神经递质功能。潜在的前提是，基因转移到大脑将防止神经元损伤，并抵消与损伤和年龄相关的记忆缺陷。基因转移治疗神经系统疾病的潜力是有希望的，但在该技术被认真考虑用于临床应用之前，大量的技术和理论问题仍有待解决。在此应用中，将研究安全有效的非病毒基因转移系统，就像在大鼠鼻中隔中一样。在我们的实验室和其他几个实验室中，最近在提高阳离子脂质粒传递系统在体内的转染效率方面取得了进展。仍然存在的挑战包括大鼠鼻中隔体内基因表达谱的完整表征，胆碱能功效的证明以及缺乏毒性。我们已经合成了一种新的基于二硫化物方法的阳离子脂质，能够在体外和体内转染神经元和胶质细胞。我们的研究结果提出了一些假设，这些假设将在本基金中得到解决，包括：1)减少载体的颗粒大小可以增加隔膜中的基因表达，这应该增加载体系统的分布并降低相关的毒性；2)非病毒介导的神经生长因子在中隔的转基因表达会增加老年动物突触前海马胆碱能神经元的大小，恢复突触前海马胆碱能功能。

DESCRIPTION (provided by applicant): The aim of this project is to develop a gene transfer procedure to repair or replace neurotransmitter function in cognitively impaired individuals. The underlying premise is that gene transfer to the brain will protect against neuronal damage as well as counteract memory related deficits associated with lesions and age-related decline. The therapeutic potential of gene transfer for neurological disease is promising, yet substantial technical and theoretical problems remain to be solved before this technology can be seriously considered for clinical application. In this application, safe and efficient non-viral gene transfer systems will be studied as in the rat septum. Progress has recently been made to improve transfection efficiency of cationic lipid-plasmid delivery systems in vivo in our laboratories and several others. Challenges remaining include a full characterization of the in vivo gene expression profile in the rat septum, demonstration of cholinergic efficacy, and lack of toxicity. We have synthesized a new cationic lipid based on a disulfide approach that is capable of transfecting neuronal and glia cells in vitro and in vivo. Our results suggest some hypotheses that will be addressed in this grant, including: 1) that gene expression in the septum can be increased by decreasing the particle size of the vector, which should increase the distribution of the vector system and decrease the associated toxicity; and 2) that non-viral mediated transgene expression of nerve growth factor in the septum will increase the size of cholinergic neurons and restore presynaptic hippocampal cholinergic function in aged animals.