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）的昼夜升高2- 到四倍，并在整个生命中保持这种高度。许多生物 DR改变终点的方向与血浆浓度升高一致 CORT。这些包括：减少细胞增殖和减弱 炎症;两个过程可能有助于降低恶性肿瘤 因此，肾上腺皮质功能亢进症可能是一个重要的 荷尔蒙触发基因表达的改变，最终阻碍 DR动物的衰老。这项建议的目的是更直接地测试 假设DR的肾上腺皮质功能亢进在其 抗衰老作用。这一目标将使用转基因技术来实现。 干预（促肾上腺皮质激素释放激素敲除[CRH-\-]小鼠） 消除了DR小鼠体内升高的CORT。这些调查人员将 CRH-/-小鼠的CORT恢复到DR水平， 在CRH-/-小鼠中作为两种独立的方法，以确保CRH的任何作用 缺乏是特定于CORT的消除，而不是其他影响， 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的作用：（1）延长 寿命和衰减的病理变化的DR。长寿研究将 测量自由采食（AL）和DR CRH-/-和CRH+/+小鼠的寿命， 补充CORT的对照组。综合病理 将获得曲线以评估CORT在可能导致 死亡，以及年龄特异性发病率和疾病进展。(2)的 DR的抗炎作用。角叉菜胶诱导的 足垫水肿及其消退将被用作 在上述实验动物组中的炎症。(3)的 DR的抗增殖作用。 垂体、胸腺、脾脏、肝脏、表皮、睾丸和肠 使用增殖细胞核抗原和溴脱氧尿苷的上皮 免疫反应性。(4)DR的降血糖/低胰岛素血症作用。 血糖和胰岛素浓度将在 上述实验动物组在整个生命周期。他们 假设CRH-/-小鼠在DR下将不能显示出 糖尿病视网膜病变的特征性低血糖和低胰岛素血症 补充CRH+/+ DR小鼠和CRH-/- AL小鼠至DR水平将 恢复这些影响。 这些研究的结果将提供最确凿的证据， 关于肾上腺皮质机能亢进是否在抗衰老作用中起作用的数据 的DR，如果是这样的话，它的作用的基本机制。

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.