HEAT SHOCK PROTEIN REGULATION WITH STRESS AND AGING

热休克蛋白对压力和衰老的调节

• 批准号: 6055455
• 负责人: KEVIN C KREGEL
• 金额: $ 28.52万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6055455
• 关键词: acidosis; age difference; aging; animal old age; chimeric proteins; exercise; flow cytometry; genetic regulation; heat stimulus; hyperthermia; immunocytochemistry; juvenile animal; laboratory rat; mature animal; oxygen consumption; physiologic stressor; stress proteins; tissue /cell culture; western blottings

Aging is associated with a general loss of ability to modulate responses to a physiological stress. The mechanisms underlying the loss of capacity of the aging organism is unclear. One area of focus is at the cellular level, where the accumulation of the highly heat-inducible 79 kDa heat shock proteins (HSP70) is associated with increased heat tolerance. These HSPs are produced in response to stressors and appear to be important in the cell's tolerance to these stressors. We have demonstrated that production of HSP70 increases in response to hyperthermia, suggesting that HSP70 may serve as a biomarker for tissues at risk from multiple physiological stressors. We have also noted that older rats are less thermotolerant to heat challenge than young rats and are less capable of generating protective HSPs. While passive hyperthermia attenuated HSP70 accumulation in older vs. young rats, exertional hyperthermia resulted in similar levels of HSPs in these groups, suggesting that the aged organism retains the ability to accumulate HSPs under certain stress conditions. thus, our guiding hypotheses are that: (a) the aged organism retains the ability to respond to stress through the accumulation of HSPS, and (b) differences in accumulation of HSP70 between young and aged organisms are the result of changes in HSP70 gene regulation. We will examine these hypotheses by: (1) determining if HSP70 accumulation is associated with cell damage following passive and exertional heat stress in senescent vs. mature and young conscious rats; (2) evaluating the effects of hyperthermia and metabolic acidosis on HSP70 synthesis in older rats using primary cell cultures derived from tissue explants; (3) examining if the patterns of translocation of HSPs to the outer cell membrane during heat and metabolic stress are altered in aged rats using flow cytometry techniques; and (4) determining if the loss of post-transcriptional regulation of the HSP gene occurs in older rats. We will use a unique integrated approach that includes whole animal, cellular, and molecular techniques to pursue basic mechanisms in the stress response. By using a variety of state-of-the-art techniques, we will be able to address important mechanistic questions involving stress protein function and regulation, cellular injury, and aging that will have widespread application to numerous clinical problems (heat, stroke, septic shock, cardiovascular disease, etc.) in the aged population. The results of this research will help us to design new therapies to protect the elderly against situations involving physiological stress, and potentially, a variety of diseases associated with aging.

衰老与调节反应能力的普遍丧失有关