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） 翻译后摘要：影响寿命的主要因素之一是环境。因此，存在生物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，当稀缺时，可以导致寿命的延长。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。正是神经系统对环境信息做出反应，引起影响寿命的生理变化。因此，调节环境信息流的小分子创造了足以延长寿命的延长寿命环境的感知。为了支持这一战略的可行性，我提出了一个原则的证明。In C.在线虫中，5-羟色胺拮抗剂米安色林阻断对食物的感知，导致让人想起饥饿的行为，并通过类似于饮食限制的机制延长寿命。然而，与此同时，米安色林导致食物摄入量急剧增加。因此，延长寿命的是米安色林通过阻断食物信号而引起的感知饥饿，而不是缺乏营养。米安色林不是通过“限制饮食”来延长寿命，而是通过“限制食物信息”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，我将识别出神经回路，这些神经回路在感知到饥饿时处理和调节寿命。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起什么作用。医学上的一些伟大成就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）。通过小分子调节感知以激活长寿机制利用了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。其核心是观察到环境通过感知间接影响寿命，感知触发影响寿命的生理变化。因此，应该有可能通过小分子来治疗与年龄有关的疾病，这些小分子以激活长寿机制的方式调节感知。