Discovery of Novel Drugs for Alzheimer's Disease,

发现治疗阿尔茨海默病的新药，

• 批准号: 6576671
• 负责人: EDWIN M MEYER
• 金额: $ 18.13万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6576671
• 关键词: Alzheimer's disease; drug discovery /isolation; drug screening /evaluation; neuroprotectants

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.

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，以修复或替代认知受损个体的神经递质功能。基本前提是，基因转移到大脑将保护神经元损伤，以及抵消与病变和年龄相关的衰退相关的记忆相关的缺陷。基因转移治疗神经系统疾病的潜力是很有希望的，但大量的技术和理论问题仍有待解决，才能认真考虑这项技术的临床应用。在本申请中，将研究安全有效的非病毒基因转移系统，如在大鼠隔中。最近，在我们的实验室和其他几个实验室中，已经在提高阳离子脂质质粒递送系统的体内转染效率方面取得了进展。仍然存在的挑战包括在大鼠隔中的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阳离子脂质的基础上的二硫化物的方法，能够在体外和体内的神经元和神经胶质细胞。我们的研究结果提出了一些将在本基金中解决的假设，包括：1）通过减小载体的颗粒尺寸可以增加隔中的基因表达，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隔中的转基因表达将增加胆碱能神经元的大小，老年动物的功能。