DIETARY RESTRICTION AND ATTENUATION OF INFLAMMATORY RESPONSE

饮食限制和炎症反应减弱

• 批准号: 6191974
• 负责人: COLLEEN J NOLAN
• 金额: $ 4.76万
• 依托单位: ST. MARY'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6191974
• 关键词: adrenocorticotropic hormone; colorimetry; corticosterone; dietary restriction; gene expression; gene induction /repression; hormone biosynthesis; hormone regulation /control mechanism; inflammation; laboratory rat; lipopolysaccharides; longevity; male; nutrition related tag; radioimmunoassay; ultracentrifugation

Dietary restriction (DR) has been demonstrated to prolong the lifespan of a number of organisms. Fischer 344 rats demonstrate a two-fold increase in plasma corticosterone (B) in response to DR which is maintained during the life span of the animal. This increase in B is related to physiological changes associated with life extension: decreased cell division, alterations in other hormones associated with nutrient allocation and endocrine regulation, and a attenuation of the inflammatory response. Together these physiological changes may be indicators of the role of B as a mediator of the ability of DR to prolong life span. The objective of this pilot proposal is to test the hypothesis that the mechanism by which DR attenuates inflammation through elevated B is to alter the secretion of B and the expression of specific genes involved in the inflammatory process. This hypothesis will be tested using the male Fischer 344 rats, an animal model commonly used in aging studies. The specific aim of this pilot project is to examine the time course of the inflammatory response in young ad libitum fed (AL) and DR rats in response to lipopolysaccharide (LPS; an inflammatory agent). The response to LPS will be measured by examining the LPS-induced rise in adrenocorticotropin (ACTH) and in the plasma. Additionally, the ability of LPS to induce the expression of genes known to be involved in the inflammatory response (inducible nitric oxide synthase and cytokines) and liver damage (as indicated by the presence of specific hepatic enzymes) will be measured. It is hypothesized that if DR does indeed prolong life span by suppressing the immune response and/or by altering the sensitivity of animals to an inflammatory agent, then the LPS-induced rises in ACTH and B, expression of genes involved in the inflammatory response and the concentration of liver specific enzymes will be decreased in DR compared to AL rats. This pilot project will provide the foundation research necessary to further explore one particular aspect through which DR prolongs provide the foundational research necessary to further explore one particular aspect through which DR prolongs life span, the role of the hypothalamic-hypophyseal-adrenal axis (HPA) in mediating the response to inflammatory challenge. If such a role is indeed elucidate, then it would add further support to the theory that dietary induced hypercorticosteronism is a key mediator of life extension.

饮食限制(DR)已被证明可以延长许多生物体的寿命。Fischer 344大鼠的血浆皮质酮(B)水平在DR的反应中增加了两倍，这种反应在动物的一生中一直保持不变。B的增加与与寿命延长相关的生理变化有关：细胞分裂减少，与营养分配和内分泌调节相关的其他激素的变化，以及炎症反应的减弱。总之，这些生理变化可能是B作为DR延长寿命能力的中介的作用的指标。这一试点方案的目的是检验这样一种假设，即DR通过升高B来减轻炎症的机制是改变B的分泌和参与炎症过程的特定基因的表达。这一假设将使用雄性费舍尔344只大鼠进行验证，费舍尔344只大鼠是衰老研究中常用的动物模型。本实验的具体目的是观察自由喂养(AL)和糖尿病视网膜病变(DR)幼鼠对内毒素(LPS；一种炎性介质)的炎症反应的时间进程。将通过检测内毒素诱导的促肾上腺皮质激素(ACTH)和血浆中促肾上腺皮质激素(ACTH)的升高来衡量对内毒素的反应。此外，还将测量内毒素诱导炎症反应(诱导型一氧化氮合酶和细胞因子)和肝损伤(由特定肝酶的存在表明)相关基因表达的能力。推测如果DR确实通过抑制免疫反应和/或改变动物对炎性介质的敏感性来延长寿命，那么与AL大鼠相比，内毒素诱导的ACTH和B升高，参与炎症反应的基因表达和肝脏特异性酶的浓度将降低。这一试点项目将提供必要的基础研究，以进一步探讨DR延长的一个特定方面，提供必要的基础研究，以进一步探讨DR延长寿命的一个特定方面，即下丘脑-垂体-肾上腺轴(HPA)在介导对炎症挑战的反应中的作用。如果这种作用真的被阐明，那么它将进一步支持饮食诱导的皮质酮增多症是延长寿命的关键媒介的理论。