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（由申请人提供） 【摘要】：环境是影响寿命的主要因素之一。因此，存在解释环境信息并将其转化为寿命变化的生物机制。例如，食物是一种环境因素，当食物匮乏时，可以延长寿命。我提出的策略旨在利用环境影响寿命的机制来治疗与年龄相关的疾病。其核心在于观察环境通过感知间接影响寿命。神经系统通过诱发影响寿命的生理变化来对环境信息做出反应。因此，调节环境信息流的小分子会产生足以延长寿命的延长寿命环境的感知。为了支持该策略的可行性，我提出了原理证明。在秀丽隐杆线虫中，血清素拮抗剂米安舍林会阻断对食物的感知，引起类似饥饿的行为，并通过类似于饮食限制的机制延长寿命。然而，与此同时，米安色林会导致食物摄入量急剧增加。因此，米安色林通过阻断食物信号而引起的饥饿感，而不是营养的缺乏，延长了寿命。米安色林不是通过“饮食限制”来延长寿命，而是通过“食物信息限制”来延长寿命。使用米安色林和其他延长寿命的分子作为工具，我将识别处理和调节寿命以应对感知饥饿的神经回路。此外，我将测试感知饥饿对年龄相关疾病模型的影响。然后我会问寿命调节神经元在神经退行性疾病的病理生理学中发挥什么作用。医学上的一些巨大成功是通过利用现有的生物功能来获得医学优势（例如疫苗接种）而取得的。通过小分子调节感知来激活长寿机制，利用现有的生物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寿命的机制来治疗与年龄相关的疾病。其核心在于观察环境通过感知间接影响寿命，从而触发影响寿命的生理变化。因此，应该可以通过小分子来调节感知，从而激活长寿机制来治疗与年龄相关的疾病。