Discovery of Novel Drugs for Alzheimer's Disease

发现治疗阿尔茨海默病的新药

• 批准号: 7687709
• 负责人: JAMES W. SIMPKINS
• 金额: $ 3万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687709
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Behavior; Brain; Cells; Drug Discovery Groups; Estrogens; Funding; Genes; Genetic; Goals; Impaired cognition; Individual; Mediating; Memory; Modeling; Modification; N-acylethanolamine; N-acylethanolamines; Nicotinic Receptors; Pharmaceutical Preparations; Prevention; Prevention approach; Production; Proteins; Research; Research Project Grants; Toxic effect; Viral; drug development; drug discovery; drug synthesis; improved; in vivo; neuroimaging; neuropathology; neuroprotection; novel; novel strategies; prevent; programs; small molecule; vector

DESCRIPTION (provided by applicant): The overall goal of this program of research is to develop novel approaches for the prevention, treatment and modeling of Alzheimer's disease (AD). This goal will be achieved through five years of funding of 4 research projects that are supported by 4 vital cores. The approach of our drug discovery group has been and will continue to be two fold. First, we believe that the effective treatment of AD may require small molecules that easily access the brain and can be administered for years to decades. As such, we have three research projects that access small molecules, for which we have evidence of neuroprotection, effects on neuropathologies of AD, effects on cognitive decline, and that readily penetrate the brain (Project by Simpkins, Project by Meyer, Project by Koulen). Further, these compounds are expected to have little or no toxicity for reasons developed in the individual projects. Project 1 will continue a long-standing effort to discover novel compounds and mechanisms for estrogen related neuroprotection. Project 2 will continue to develop their well established program for understanding of how brain alpha7 nicotinic receptors both improve memory related behaviors and protect cells from a variety of toxic insults. Project 5 is a new research project that will identify components and mechanisms of neuroprotection mediated by N-Acylethanolamines and identify potential candidates from this group of compounds for drug development. The second strategy that we have used for drug discovery has been genetic, both for treating as well as modeling AD. We believe that ultimately, the prevention/treatment of AD may require genetic modification to replace missing or defective proteins, or reduce the production of over-expressed proteins. We have projects that use viral (Project 4) vectors for in vivo transfer of model genes, genes that produce certain aspects of AD neuropathology, and genes that are expected to prevent/treat the neuropathology of AD. The 4 supportive cores are Administrative (Core A), Vector Core (Core B), Neuroimaging Core (Core C) and Drug Synthesis Core (Core D). Collectively, this program of research will continue our successful efforts to discover novel compounds and approaches for the prevention, treatment and modeling of AD.

描述（由申请人提供）：该研究计划的总体目标是开发预防、治疗和建模阿尔茨海默病（AD）的新方法。这一目标将通过为期五年的 4 个研究项目的资助来实现，这些项目由 4 个重要核心支持。我们的药物发现小组的方法已经并将继续是双重的。首先，我们认为有效治疗 AD 可能需要易于进入大脑并可以持续数年至数十年的小分子。因此，我们有三个接触小分子的研究项目，我们有证据表明这些小分子具有神经保护作用、对 AD 神经病理学的影响、对认知能力下降的影响，并且很容易渗透到大脑中（Simpkins 的项目、Meyer 的项目、Koulen 的项目） ）。此外，由于各个项目中开发的原因，预计这些化合物几乎没有毒性或没有毒性。项目 1 将继续长期努力发现雌激素相关神经保护的新化合物和机制。 Project 2 将继续开发其完善的计划，以了解大脑 α7 烟碱受体如何改善记忆相关行为并保护细胞免受各种毒性损伤。项目 5 是一个新的研究项目，将确定 N-酰基乙醇胺介导的神经保护成分和机制，并从这组化合物中确定用于药物开发的潜在候选药物。我们用于药物发现的第二个策略是遗传策略，既用于治疗 AD，也用于建模 AD。我们相信，最终，AD 的预防/治疗可能需要基因改造来替换缺失或有缺陷的蛋白质，或减少过度表达蛋白质的产生。我们的项目使用病毒（项目 4）载体体内转移模型基因、产生 AD 神经病理学某些方面的基因，以及预期预防/治疗 AD 神经病理学的基因。 4 个支持核心是管理（核心 A）、矢量核心（核心 B）、神经影像核心（核心 C）和药物合成核心（核心 D）。总的来说，该研究计划将继续我们的成功努力，发现用于预防、治疗和建模 AD 的新化合物和方法。