TRANSGENIC PROBES OF GLUCOCORTICOID INVOLVEMENT IN AGING

描述：(改编自应用程序)：饮食限制(DR) 增加血浆游离皮质酮(CORT)的每日升高2- 至四倍，并在一生中保持这一高度。许多生物 DR改变终点的方向与升高的血浆方向一致 科特。这些包括：减少细胞增殖和减弱 炎症；可能有助于降低恶性程度的两个过程 因此，肾上腺皮质功能亢进症的病理生理学可能是一个重要的 荷尔蒙触发改变的基因表达，最终延缓 DR动物的衰老。这项提议的目的是更直接地进行测试 认为DR的肾上腺皮质功能亢进在其发病中起作用的假说 抗衰老作用。这一目标将通过转基因技术实现。 干预(促肾上腺皮质激素释放激素基因敲除小鼠) 这消除了DR小鼠体内皮质醇的升高。这些调查人员将 还可以将CRH-/-小鼠的皮质醇水平恢复到DR水平，并将皮质醇水平提高到DR水平 在CRH-/-小鼠中作为两种独立的手段来确保CRH的任何作用 缺乏是由于皮质醇的消除，而不是由于 CRH缺乏症。具体目标是使用这些干预措施来评估 DR诱导的肾上腺皮质功能亢进在以下方面的作用：(1)延长 长寿博士对生命和减轻病变的研究将 测量随意喂养(AL)和DR CRH-/-和CRH+/+小鼠的寿命， 皮质醇补充对照组。综合病理学 将获得配置文件，以评估CORT在可能的原因中的作用 死亡以及特定年龄段的发病率和疾病进展。(2) 丹参的抗炎作用角叉菜胶致炎症的时程研究 足底浮肿及其消退情况将作为 上述实验动物组均有炎症反应。(3) Dr.Cell增殖的抗增殖作用将在 垂体、胸腺、脾、肝、表皮、睾丸和肠道 应用增殖细胞核抗原和溴脱氧尿嘧啶核苷培养上皮细胞 免疫反应性。(4)DR的降血糖/低血糖作用。 血糖和胰岛素浓度将在 上述实验动物组贯穿整个生命周期。他们 假设DR下的CRH-/-小鼠不能表现出 糖尿病视网膜病变的特征性低血糖和低胰岛素血症 CRH+/+DR小鼠和CRH-/-AL小鼠补充到DR水平将 恢复这些效果。 这些研究的结果将提供最确凿的证据 关于肾上腺皮质功能亢进是否在抗衰老作用中起作用的数据 以及，如果是的话，关于其作用的基本机制。

DESCRIPTION: (adapted from the application): Dietary restriction (DR) increases the diurnal elevation of plasma free corticosterone (CORT) two- to-four fold and maintains this elevation throughout life. Many biological endpoints are changed by DR in a direction consistent with elevated plasma CORT. These include: reduced cell proliferation and attenuated inflammation; two processes that may contribute to the reduced malignancy and pathophysiology of DR. Hyperadrenocorticism may thus be an important hormonal trigger of the altered gene expression that ultimately retards aging in DR animals. The object of this proposal is to test more directly the hypothesis that the hyperadrenocorticism of DR plays a role in its anti-aging actions. This objective will be accomplished using a transgenic intervention (Corticotrophin Releasing Hormone knockout [CRH-\-] mouse) that eliminates the elevated CORT in DR mice. These investigators will also restore CORT to DR levels in CRH-/- mice and raise CORT to DR levels in CRH-/- mice as two independent means to ensure that any effects of CRH deficiency are specific to elimination of CORT and not to other effects of CRH deficiency. The specific aims are to use thee interventions to assess the role of DR-induced hyperadrenocorticism in: (1) The prolongation of life and attenuation of pathological changes by DR. Longevity studies will measure life span in ad libitum (AL) fed and DR CRH-/- and CRH+/+ MICE, and in CORT supplemented control groups. Comprehensive pathological profiles will be obtained to assess the role of CORT in probably cause of death, and in age-specific incidence and progression of disease. (2) The anti-inflammatory action of DR. The time-course of carrageenan-induced foot pad edema and its resolution will be used as the index of inflammation in the aforementioned experimental animal groups. (3) The anti-proliferative actions of DR. Cell proliferation will be measured in pituitary, thymus, spleen, liver, epidermis, testis, and intestinal epithelia using proliferating cell nuclear antigen and bromodeoxyuridine immunoreactivity. (4) The hypoglycemic/hypoinsulinemic effects of DR. Blood glucose and insulin concentrations will be measured in the aforementioned experimental animal groups throughout life span. They hypothesize that the CRH-/- mice under DR will fail to show the characteristic hypoglycemia and hypoinsulinemia of DR but that CORT supplementation of CRH+/+ DR mice and CRH-/- AL mice to DR levels will restore these effects. The results of these studies will provide the most conclusive evidence to data on whether hyperadrenocorticism plays a role in the anti-aging action of DR and, if so, on the underlying mechanisms through which it acts.