Role of Neuropeptide S in age-related cognitive decline

神经肽 S 在年龄相关认知能力下降中的作用

• 批准号: 8096345
• 负责人: RAINER K REINSCHEID
• 金额: $ 18.15万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096345
• 关键词: Address; Affect; Age; Age-associated memory impairment; Aged, 80 and over; Aging; Agonist; Alleles; Animal Model; Anxiety; Arousal; Attenuated; Behavioral; Biochemical; Biological; Biological Assay; Brain; Brain region; Caregivers; Code; Cognition; Cognitive; Cognitive aging; Cyclic AMP; Data; Dementia; Deterioration; Development; Drug Delivery Systems; Elderly; Enrollment; Environmental Risk Factor; Event; Frequencies; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Health Care Costs; Healthcare Systems; Hippocampal Formation; Human; Impaired cognition; Impairment; In Vitro; Individual; Intervention; Knockout Mice; Knowledge; Lead; Learning; Life; Longevity; MAP Kinase Gene; Measures; Memory; Memory Loss; Memory impairment; Modeling; Molecular Genetics; Mus; Mutation; Nature; Neurodegenerative Disorders; Neuropeptides; Neurotransmitters; Oxidative Stress; Participant; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Population; Positioning Attribute; Prevention; Protein Isoforms; Psyche structure; Quality of life; Receptor Gene; Regulation; Relative (related person); Reporting; Research; Risk; Rodent; Role; Signal Transduction; Single Nucleotide Polymorphism; Sleep; Societies; Symptoms; System; Technology; Testing; Therapeutic Intervention; Time; Translating; Variant; Wakefulness; age related; aged; aging brain; base; cognitive function; cohort; genetic association; healthy aging; interest; juvenile animal; member; neural circuit; neurobiological mechanism; neuromechanism; new therapeutic target; novel; object recognition; receptor; receptor sensitivity; stable cell line; tool; translational approach

DESCRIPTION (provided by applicant): As our society grows progressively older, age-related memory loss is posing an increasing problem, not only for quality of life of elderly people, but also for relatives, caregivers and the health care system in general. While the biological mechanisms of cognitive decline are poorly understood, both environmental and genetic factors are known to contribute. It is therefore important to understand how the brain and one of its major functions, i.e. memory, age during human life and identify specific biochemical targets and mechanisms that are associated with age-related impairment of learning and memory. Neuropeptide S (NPS) is a recently identified transmitter in the brain. NPS produces arousal and wakefulness and reduces behavioral signs of anxiety in rodents. Recent studies in our lab demonstrate that NPS can potently enhance learning and memory. A naturally occurring mutation in the human NPS receptor gene changes the sensitivity of the receptor significantly, which may have a behavioral impact on memory. These evidences make the NPS system an interesting candidate for development of new drugs with pro-cognitive effects that can help to alleviate symptoms of age-related memory decline. The first part of this proposal will test the effects of NPS on memory formation in very old mice, which are an established model to study age-related memory deficits. Since NPS can enhance memory formation in young mice, we expect to see similar effects in aged mice. Second, we will analyze the pharmacology and signal transduction of a number of naturally occurring variants of the human NPS receptor in order to identify particular versions of the gene that respond differently to activation by NPS. Since these mutations in the NPS receptor occur with high frequency in the human population, we will next address the question whether different forms of the receptor may contribute to age-related cognitive decline or exert a protective function. For this part of the study, we will analyze NPS receptor genotypes in participants of a very large geriatric study: the "90+ Study". We will specifically test whether more sensitive or attenuated NPS receptor gene variants are associated with memory performance, onset and progression of memory decline, or other mental capabilities in these oldest-old members of our society (over 90 years old at time of enrollment). Together, we intend to validate the NPS system as a novel drug target for treatment of age-related cognitive decline. Results from these studies will greatly advance our knowledge about neural mechanisms underlying cognitive aging. PUBLIC HEALTH RELEVANCE: Age-related cognitive decline is a tremendous burden for affected individuals, society, and the health care system, while the underlying neurobiological mechanisms remain largely unknown. In the current proposal, we plan to use translational animal models, in vitro pharmacology, and human molecular genetic tools to explore the potential of the Neuropeptide S system as an emerging target for treatment of age-related cognitive decline. Analyzing naturally occurring polymorphisms in the human NPS receptor gene that are associated with cognitive performance may have practical implications to assess individual risk for developing cognitive decline that would warrant early prevention. The study is both exploratory and translational and could lead to a better understanding of neural mechanisms underlying cognitive aging.

描述（由申请人提供）：随着我们社会的逐渐增长，与年龄相关的记忆丧失构成了一个越来越多的问题，不仅是老年人的生活质量，而且对于亲戚，照顾者和医疗保健系统而言。虽然认知下降的生物学机制知之甚少，但已知环境和遗传因素均可促成。因此，重要的是要了解大脑及其主要功能之一，即记忆，人类生活中的年龄，并确定与与年龄相关的学习和记忆障碍相关的特定生化目标和机制。 神经肽S（NP）是大脑中最近被鉴定出的发射器。 NP会产生唤醒和清醒，并减少啮齿动物焦虑的行为迹象。我们实验室的最新研究表明，NP可以有效增强学习和记忆。人NPS受体基因中天然存在的突变会显着改变受体的敏感性，这可能对记忆产生行为影响。这些证据使NPS系统成为开发具有积极认知作用的新药的有趣候选者，可以帮助减轻与年龄相关的记忆下降的症状。该提案的第一部分将测试NP对非常古老的小鼠记忆形成的影响，这是研究与年龄相关的记忆缺陷的既定模型。由于NP可以增强小鼠的记忆形成，因此我们希望在老年小鼠中看到相似的作用。其次，我们将分析人类NPS受体的许多天然变体的药理学和信号转导，以识别基因的特定版本，这些基因对NP的激活有所不同。由于NPS受体中的这些突变发生在人口中的高频中，因此我们接下来将解决以下问题，不同形式的受体是否可能导致与年龄相关的认知能力下降或发挥保护功能。在这一研究的这一部分中，我们将分析一项非常大的老年研究参与者中的NPS受体基因型：“ 90+研究”。我们将特别测试更敏感或减弱的NPS受体基因变体与记忆力的表现，记忆下降和进展的记忆下降和进展有关，还是我们社会中这些最古老的成员（在注册时年龄超过90年）中的其他精神能力。我们共同打算验证NPS系统，作为治疗与年龄相关的认知下降的新药物。这些研究的结果将大大提高我们对认知衰老潜在的神经机制的了解。 公共卫生相关性：与年龄相关的认知下降是受影响个人，社会和医疗保健系统的巨大负担，而潜在的神经生物学机制仍然在很大程度上未知。在当前的建议中，我们计划使用转化动物模型，体外药理学和人分子遗传工具来探索神经肽系统的潜力，作为治疗与年龄相关的认知下降的新兴靶标。分析与认知性能相关的人类NP受体基因中自然发生的多态性可能具有实际意义，以评估个人出现认知下降的风险，这将需要早期预防。这项研究既是探索性的，又是转化的，可以更好地了解认知衰老的神经机制。