Modulation of Sensory Perception to Treat Age Related Disease

调节感官知觉来治疗与年龄相关的疾病

• 批准号: 8145486
• 负责人: Michael Petrascheck
• 金额: $ 284.25万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145486
• 关键词: Affect; Behavior; Biological; Biological Process; Caenorhabditis elegans; Disease; Eating; Environment; Environmental Risk Factor; Food; Longevity; Medical; Medicine; Mianserin; Modeling; Nervous system structure; Neurodegenerative Disorders; Neurons; Nutrient; Perception; Physiological; Play; Process; Role; Sensory; Serotonin Antagonists; Signal Transduction; Starvation; Testing; Time; Translating; Vaccination; abstracting; age related; dietary restriction; neural circuit; public health relevance; response; small molecule; success; tool

DESCRIPTION (Provided by the applicant) Abstract: One of the major factors affecting lifespan is the environment. Therefore, biological mechanisms exist to interpret environmental information and translate it into changes in lifespan. Food, for example, is one environmental factor that when scarce can result in an extension of lifespan. The strategy I am presenting aims to exploit the mechanisms by which the environment influences lifespan to treat age-related disease. At its core lies the observation that the environment influences lifespan indirectly through perception. It is the nervous system that responds to environmental information by inducing physiological changes that affect lifespan. Therefore small molecules that modulate the flow of environmental information create the perception of a lifespan extending environment which is sufficient to extend lifespan. To support the feasibility of this strategy I present a proof of principle. In C. elegans, the serotonin antagonist Mianserin blocks the perception of food, causes behaviors that are reminiscent of starvation and extends lifespan by mechanisms similar to those of dietary restriction. However, at the same time, Mianserin causes a dramatic increase in food intake. Therefore it is the perceived starvation, caused by Mianserin by blocking food signals, rather than the lack of nutrients, that extends lifespan. Instead of extending lifespan by ""dietary restriction"", Mianserin extends lifespan by ""food-information restriction."" Using Mianserin and other lifespan extending molecules as tools, I will identify neural circuits that process and regulate lifespan in response to perceived starvation. Furthermore, I will test the effect of perceived starvation on models of age-related disease. I will then ask what role lifespan-regulating-neurons play in the pathopysiology of neurodegenerative disease. Some of the great successes in medicine were achieved by exploiting existing biological functions to gain medical advantages (e.g. vaccination). Modulation of perception by small molecules to activate mechanisms of longevity exploits an existing biological function to treat age-related disease. Public Health Relevance: The strategy I am presenting aims to exploit the mechanisms by which the environment influences lifespan to treat age-related disease. At its core lies the observation that the environment influences lifespan indirectly through perception which triggers physiological changes that affect lifespan. Therefore, it should be possible to treat age-related diseases by small molecules that modulate perception in ways that activate mechanisms of longevity.

描述（申请人提供） 摘要：影响寿命的主要因素之一是环境。因此，存在生物学机制来解释环境信息并将其转化为寿命的变化。例如，食物是一个环境因素，当稀缺会导致寿命延长时。我提出的策略旨在利用环境影响与年龄相关疾病的寿命的机制。以此为核心，观察到环境通过感知间接影响寿命。正是神经系统通过诱导影响寿命的生理变化来响应环境信息。因此，调节环境信息流的小分子产生了对延长寿命的寿命延长寿命的感知。为了支持这种策略的可行性，我提出了原则证明。在秀丽隐杆线虫中，5-羟色胺拮抗剂米亚梅蛋白阻止了食物的感知，引起了让人联想到饥饿的行为，并通过与饮食限制的机制延长了寿命。但是，与此同时，米安梅林会导致食物摄入量的急剧增加。因此，是由木瑟蛋白通过阻止食物信号而不是缺乏营养的饥饿感而延长寿命的原因。 Mianserin并没有通过“饮食限制”延长寿命，而是通过“食物信息限制”延长了寿命。“使用Mianserin和其他寿命将分子扩展为工具，我将确定这些神经回路的神经回路，并调节对感知饥饿的响应生命周期。此外，我将测试感知到的饥饿对年龄相关疾病模型的影响。然后，我将询问在神经退行性疾病的病原体生物生物学中，寿命调节神经元的作用是什么。通过利用现有的生物学功能获得医疗优势（例如疫苗接种），可以取得一些巨大的成功。小分子对感知激活寿命机制的调节可利用现有的生物学功能来治疗与年龄相关的疾病。 公共卫生相关性：我提出的策略旨在利用环境影响与年龄相关疾病的生命周期的机制。核心的观察是，环境通过感知间接影响寿命，这会触发影响寿命的生理变化。因此，应该通过小分子来治疗与年龄相关的疾病，以激活寿命机制的方式调节感知。