HEAT SHOCK PROTEIN REGULATION WITH STRESS AND AGING

衰老与调节反应能力的全面丧失有关 一种生理压力。造成这一损失的机制 老化的生物体的能力尚不清楚。其中一个关注的领域是 细胞水平，在那里积累的高度可热诱导的79 KDA热休克蛋白(HSP70)与高热有关 宽容。这些热休克蛋白是对应激源的反应而产生的，并出现 重要的是细胞对这些应激源的耐受性。我们有 证明热休克蛋白70的产生增加是对 体温过高，提示HSP70可能作为组织的生物标志物 面临多种生理压力的风险。我们也注意到， 老年大鼠对高温挑战的耐受性比年轻大鼠低，而且 产生保护性热休克蛋白的能力较弱。虽然是被动的 高温降低了老年大鼠与年轻大鼠中HSP70的积聚。 运动性高热导致这些患者体内HSPs水平相似 群体，这表明老年有机体保留了 在一定的应激条件下积累热休克蛋白。因此，我们的指导 假设是：(A)衰老的生物体保留了 通过热休克蛋白的积累来应对压力，以及(B)差异 在年轻和老年生物体之间积累HSP70是结果 HSP70基因调控的变化。我们将检验这些假设 通过：(1)确定HSP70的积聚是否与细胞损伤有关 衰老期与成熟期和成熟期的被动和劳累热应激 (2)观察热疗对小鼠的影响。 利用原代细胞研究代谢性酸中毒对老年大鼠HSP70合成的影响 来自组织外植体的培养；(3)检查 热休克蛋白在受热过程中移位到外细胞膜 用流式细胞术检测老年大鼠代谢应激的改变 技术；以及(4)确定转录后缺失 热休克蛋白基因的调节发生在老年大鼠身上。 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，以追求基本的机制 压力反应。通过使用各种最先进的技术，我们 将能够解决与压力有关的重要机械问题 蛋白质的功能和调节、细胞损伤和衰老 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。这个 这项研究的结果将有助于我们设计新的治疗方法来保护 老年人应对涉及生理压力的情况，以及 潜在的，与衰老相关的各种疾病。

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.