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: 6372124
• 负责人: KEVIN C KREGEL
• 金额: $ 29.87万
• 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 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6372124
• 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 一种生理压力。 丧失的机制 衰老机体的能力尚不清楚。 其中一个重点领域是 细胞水平，其中高度热诱导79 kDa热休克蛋白（HSP 70）与增加的热 宽容 这些热休克蛋白是对压力源的反应， 在细胞对这些应激源的耐受性中起着重要作用。 我们有 表明HSP 70的产生增加， 热疗，表明热休克蛋白70可作为生物标志物的组织 处于多种生理压力的危险中 我们也注意到 老年大鼠对热攻击的耐热性低于年轻大鼠， 产生保护性热休克蛋白的能力较低。而被动 高温减弱了老年大鼠与年轻大鼠中HSP 70的积累， 运动性体温过高导致这些人的热休克蛋白水平相似， 组，这表明老年人的有机体保留的能力， 在一定的胁迫条件下积累HSP。 因此， 假设是：（a）老化的生物体保留了以下能力： 通过HSPS的积累响应胁迫，和（B）差异 在年轻和老年生物体之间的HSP 70积累是结果 HSP 70基因调控的变化。 我们将检验这些假设 通过：（1）确定HSP 70积累是否与细胞损伤相关 在衰老与成熟的被动和劳力性热应激后， 年轻清醒大鼠;（2）评估高温的影响， 代谢性酸中毒对老年大鼠HSP 70合成的影响 组织外植体培养;（3）检查是否有 热休克蛋白的易位到细胞外膜在加热和 用流式细胞术检测老年大鼠代谢应激的改变 技术;和（4）确定是否转录后的损失 HSP基因的调节发生在老年大鼠中。 我们将使用一种独特的综合方法，包括整个动物， 细胞和分子技术，以追求基本机制， 应激反应 通过使用各种最先进的技术，我们 将能够解决涉及压力的重要机械问题 蛋白质功能和调节，细胞损伤，以及老化， 广泛应用于许多临床问题（中暑、中风， 感染性休克、心血管疾病等）在老年人口中。 的 这项研究的结果将有助于我们设计新的治疗方法， 老年人应对涉及生理压力的情况， 潜在的，与衰老有关的各种疾病。