Inflammation and Aging-associated Diabetes

炎症和衰老相关的糖尿病

• 批准号: 10617749
• 负责人: DANICA CHEN
• 金额: $ 38.73万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617749
• 关键词: Acetylation; Affect; Age; Aging; Biochemical; Biochemical Pathway; Biology; Cell Culture Techniques; Cells; Chronic; Chronic Disease; Cues; Deacetylase; Deacetylation; Deterioration; Development; Diabetes Mellitus; Disease; Drug Targeting; Elderly; Event; Genetic; Goals; Health; Homeostasis; Human; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Innate Immune Response; Insulin Resistance; Knockout Mice; Link; Longevity; Macrophage; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Mus; Nutrient; Nutritional status; Overnutrition; Pathway interactions; Physiological; Play; Predisposition; Regulation; Risk Factors; Role; Sampling; Sirtuins; System; Testing; Therapeutic; Time; Tissues; aged; aging nutrition; clinic ready; combat; drug development; epidemiology study; feasibility testing; gain of function; genetic manipulation; healthspan; in vivo; mouse model; nicotinamide-beta-riboside; novel; novel strategies; sensor; systemic inflammatory response

Project Summary Epidemiological studies indicate that aging is associated with a chronic increase in circulating levels of inflammatory molecules. Chronic inflammation has been linked to major aging-related changes and numerous aging-related chronic diseases, including diabetes. The overarching goal of this proposal is to elucidate the molecular and cellular mechanisms underlying aging-associated chronic inflammation and the development of diabetes. Nutritional status affects chronic inflammation, the rate of aging, and the development of aging related chronic diseases, suggesting a possible crosstalk between chronic inflammation regulated by physiological aging and nutritional status. We hypothesize that nutrient sensors regulate the inflammatory response pathways and provide a crosstalk between chronic inflammation regulated by physiological aging and nutritional status. This hypothesis is supported by our recent findings that a nutrient sensor regulates a key component of the inflammatory response pathway and is responsive to both physiological aging and nutritional status. We propose that the nutrient sensitive inflammatory response pathway forms the molecular interface between nutrient input and the metabolic network. Through this interface, cells can respond readily to metabolic and external cues, and dynamically regulate the metabolic status. Perturbation of this interface contributes to aging-associated chronic inflammation and diseases, such as diabetes. We have established mouse models to study chronic inflammation and metabolic perturbation during aging and overnutrition. We have also established a cell-based system to study aging- or overnutrition-associated inflammatory response in mechanistic details. Using the established system, we will elucidate the molecular events that result in increased chronic inflammation during aging or overnutrition. Using a gain-of-function approach, we will test the feasibility of activating these molecules to dampen aging or overnutrition-associated chronic inflammation and insulin resistance. Collectively, these studies highlight a novel nutrient sensitive inflammatory response pathway, which maintains metabolic homeostasis and is perturbed by overnutrition and physiological aging, thus is highly relevant to human health. The factors identified in our study are likely to play paramount roles in limiting chronic inflammation and suggest new approaches to combat chronic inflammation-related deterioration and diseases, such as diabetes.

项目摘要 流行病学研究表明，衰老与血液循环中的 炎症分子慢性炎症与主要的衰老相关变化有关， 许多与衰老有关的慢性疾病，包括糖尿病。本提案的总体目标是 阐明衰老相关慢性炎症的分子和细胞机制 和糖尿病的发展。营养状况影响慢性炎症、衰老速度， 以及与衰老相关的慢性疾病的发展，这表明 由生理老化和营养状况调节的慢性炎症。我们假设 营养传感器调节炎症反应途径， 由生理老化和营养状况调节的慢性炎症。这种假设是 我们最近的发现支持了这一点，即营养传感器调节炎症的关键成分， 反应途径，并对生理老化和营养状况作出反应。我们提出 营养敏感性炎症反应途径形成了 营养输入和代谢网络。通过这个接口，细胞可以很容易地响应 代谢和外部线索，并动态调节代谢状态。这种扰动 界面有助于衰老相关的慢性炎症和疾病，如糖尿病。 我们已经建立了小鼠模型来研究慢性炎症和代谢紊乱， 衰老和营养过剩我们还建立了一个基于细胞的系统来研究衰老--或者 营养过剩相关的炎症反应的机制细节。利用已建立的系统， 我们将阐明在衰老过程中导致慢性炎症增加的分子事件， 营养过剩使用功能增益方法，我们将测试激活这些功能的可行性。 分子来抑制衰老或营养过剩相关的慢性炎症和胰岛素抵抗。 总的来说，这些研究强调了一种新的营养敏感性炎症反应途径， 维持代谢平衡，并受到营养过剩和生理衰老的干扰，因此， 与人类健康密切相关。在我们的研究中确定的因素很可能发挥至关重要的作用 在限制慢性炎症和建议新的方法来对抗慢性炎症相关的 疾病，如糖尿病。