SYSTEMATIC AND CELLULAR INDICIES OF STRESS IN OBESITY

肥胖压力的系统和细胞指标

• 批准号: 6301769
• 负责人: Michael Koban
• 金额: $ 7.78万
• 依托单位: MORGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6301769
• 关键词: blood pressure; cardiovascular system; cell biology; electrocardiography; enzyme activity; heart rate; hemodynamics; high performance liquid chromatography; homeostasis; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; immunocytochemistry; immunologic assay /test; in situ hybridization; laboratory rat; neuroendocrine system; northern blottings; obesity; physiologic stressor; pituitary thyroid axis; stress proteins; telemetry; western blottings

Description (Adapted from Application): The long-term goal is to better understand the homeostatic responsiveness of vertebrates to stress. It is proposed to use a rat model of human pathophysiology, specifically obesity, to investigate how systemic and cellular responsiveness is altered during stress. Sleep deprivation will be employed as the stress paradigm on the genetically obese (fa/fa) and lean (Fa/?) Zucker rat. With this model, the PI will examine neuroendocrine and cardiovascular indices of stress involving four homeostatic systems: (1) the hypothalamic-pituitary-thyroid (HPT) axis; (3) the sympathoadrenal (SA) system, including endocrine pancreas; and (4) hemodynamic parameters of the cardiovascular (CV) system. The specific aims are: (1) to characterize and compare neuroendocrine responsiveness by determining tissue and plasma levels of HPA axis hormones (CRF, ACTH, prolactin, and corticosterone); HPT axis (TRF, TSH, and thyroid hormones, including both total and free components); and SA system hormones (NE, E, DA; and catecholamine synthesizing enzymes); (2) to determine the hemodynamic responsiveness of the CV system by measuring mean arterial pressure, heart rate, respiratory rate, and electrocardiogram waveforms; (3) to measure cellular responsiveness to stress by determining changes in expression of stress-related genes (heat-shock genes); and (4) to measure changes in activities of rate-limiting enzymes of key metabolic of key metabolic pathways as an index of change in cellular carbon flow and energy utilization. Experimental approaches for aims 1 and 3 will be to use immunoassay, Western blots, Northern blots, immunocytochemistry, in situ hybridization, and HPLC for specific localization and quantitative determination of the designated analyses. Aim 2 will be accomplished by implantation of radiotelemetry devices to measure cardiovascular parameters. Little is known about how stress affects a rat model with a disorder characteristic of many humans, obesity. The working hypotheses is as follows: Given the morbidity observed when a potent stressor is applied chronically to normal lean animals, it is hypothesized that obesity, with its own underlying pathologies that also lead to morbidity, will result in a significantly shorter time course of homeostatic responsiveness compared to lean animals and that the responsiveness will be greater in magnitude compared to lean animals. These predicted observations will be consistent with the overall decline of the health of stressed animals, indicating that homeostatically, the obese phenotype is in markedly greater physiological distress.

描述（改编自应用程序）：长期目标是更好地 了解脊椎动物对压力的自我平衡反应。它 建议使用人类病理生理学的大鼠模型，具体而言， 肥胖症，以研究系统和细胞的反应是如何 在压力下改变。睡眠剥夺将被用作压力 遗传性肥胖（fa/fa）和瘦（Fa/？）老鼠 通过该模型，PI将检查神经内分泌和心血管 压力指数涉及四个稳态系统：（1） 下丘脑-垂体-甲状腺（HPT）轴;（3）交感肾上腺（SA）轴 系统，包括内分泌胰腺;和（4）血液动力学参数 心血管（CV）系统。具体目标是：（1） 通过测定来表征和比较神经内分泌反应性 组织和血浆HPA轴激素（CRF、ACTH、催乳素和 皮质酮）; HPT轴（TRF，TSH和甲状腺激素，包括 总组分和游离组分）;和SA系统激素（NE、E、DA;和 儿茶酚胺合成酶）;（2）测定血流动力学 通过测量平均动脉压来测量CV系统的反应性， 心率、呼吸频率和心电图波形;（3） 测量细胞对压力的反应， 应激相关基因（热激基因）的表达;和（4） 测量关键代谢产物限速酶活性的变化， 作为细胞碳流变化的指标 和能源利用。目标1和目标3的实验性办法将 可以使用免疫测定、蛋白质印迹、北方印迹， 免疫细胞化学、原位杂交和HPLC检测特异性 指定分析的定位和定量测定。 目标2将通过植入无线电遥测装置来实现， 测量心血管参数。 关于压力如何影响患有疾病的大鼠模型知之甚少 肥胖是许多人类的特征工作假设是， 如下：考虑到当施加强有力的压力时观察到的发病率 慢性地对正常瘦动物，假设肥胖， 其自身的潜在病理也会导致发病， 导致体内平衡的时间过程显著缩短 与瘦型动物相比， 在数量上比瘦的动物更大。这些预测 观察结果将与健康状况的总体下降一致 这表明，从体内平衡的角度来看， 表型在明显更大的生理痛苦。