Biologic approach to targeting a nicotinic receptor accessory molecule for cognit

描述(由申请人提供)： 拟议的项目详细介绍了一种以胆碱能系统的尼古丁受体为治疗靶点的生物策略，用于治疗精神和神经疾病。胆碱能系统是一种重要的调节性神经递质系统，调节奖赏、学习记忆、注意力和认知功能。烟碱型乙酰胆碱受体是胆碱能系统的主要受体，受调节的辅助蛋白调节，与烟碱型乙酰胆碱受体结合并抑制其功能。在我们的小鼠模型中进行的概念研究的生物学证据表明，调节胆碱能张力有利于增强大脑中复杂的电路，从而增强学习和记忆功能。为了开发一种概括这种认知增强的治疗干预方法，我们建议开发一种生物治疗方法，通过尼古丁受体的辅助分子来增强大脑中的胆碱能张力。由于血脑屏障是大分子向脑内神经元递送所面临的最具挑战性的问题，我们提出了几种基于多肽的优化递送策略，这些多肽被证明有能力将治疗候选物质运送到血脑屏障之外。我们将结合最高效的移位器。我们将在我们已建立的尼古丁受体细胞系和检测方法上测试候选治疗药物的功能抑制。此外，我们将标记潜在的载体分子，以评估它们的血脑穿透能力，并最终在我们的小鼠模型中测试候选分子的疗效。如果成功，这一结果将导致开发一种治疗候选药物，用于治疗与精神和神经疾病相关的认知和记忆障碍，如精神分裂症、阿尔茨海默氏症和帕金森氏症以及抑郁症。 公共卫生相关性： 该项目涉及开发治疗干预措施，以治疗与精神和神经疾病相关的认知功能障碍，如精神分裂症、阿尔茨海默病、帕金森病、抑郁症和ADHD。

DESCRIPTION (provided by applicant): The proposed project details a biologic strategy for the therapeutic targeting of nicotinic receptors of the cholinergic system for the treatment of mental and neurological disorders. The cholinergic system is an important modulatory neurotransmitter system, regulating reward, learning and memory, attention, and cognitive functions. The nicotinic acetylcholine receptor, a major receptor of the cholinergic system, is regulated by modulatory accessory proteins which bind to nicotinic acetylcholine receptors and dampen their function. Biological proof of concept studies in our mouse models indicate that regulating cholinergic tone has a beneficial enhancement of complex circuits in the brain, leading to enhanced learning and memory function. In order to develop a therapeutic intervention recapitulating this cognitive enhancement, we propose to develop a biological therapeutic to enhance cholinergic tone in the brain through accessory molecules to nicotinic receptors. Because the blood brain barrier is the most challenging problem facing the delivery of the macromolecules to neurons in the brain, we propose several strategies for optimizing delivery based on peptides with demonstrated ability to deliver therapeutic candidates past the blood- brain barrier. We will couple the most efficient translocators. We will test the functional inhibition by therapeutic candidates on our established nicotinic receptor cell lines and assays. In addition, we will label potential carrier molecules to assess their blood-brain penetrability, and finally test the efficacy of candidates in vivo in our mouse models. If successful the outcome will lead to the development of a therapeutic candidate to treat cognitive and memory impairments associated with mental and neurological disorders, such as schizophrenia, Alzheimer's and Parkinson's disease, and depression. PUBLIC HEALTH RELEVANCE: This project involves the development of therapeutic interventions to treat the cognitive dysfunction associated with mental and neurological disorders, such as schizophrenia, Alzheimer's disease, Parkinson's disease, depression, and ADHD.