Tissue Sensitivity to Stress in The Absence of HSP70

缺乏 HSP70 时组织对压力的敏感性

• 批准号: 6985821
• 负责人: CLAYTON R HUNT
• 金额: $ 6.89万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985821
• 关键词: acetaminophen; aging; alanine transaminase; apoptosis; cellular pathology; drug adverse effect; enzyme activity; gene expression; heat shock proteins; hepatotoxin; immunocytochemistry; kidney disorder; laboratory mouse; light microscopy; liver function; physiologic stressor; protein biosynthesis; renal ischemia /hypoxia; renal toxin; reperfusion; terminal nick end labeling; western blottings

DESCRIPTION (provided by applicant): Aging is characterized by an increasing inability of the organism to respond to ordinary and extra-ordinary stress at both the cellular and organized tissue level. Coincident with the diminished stress response are associated alterations in gene expression that probably contribute to the underlying mechanism. Among the genes whose expression has been demonstrated to decline with age, both in vivo and in vitro, is the 70 Kd heat shock protein (HSP70). Identified originally as the major protein synthesized after hyperthermia, HSP70 is now known to be synthesized in response to a wide range of exogenous stresses including toxins and drugs. More importantly HSP70 is expressed in tissues that are exposed to stress, either as part of their normal physiological function or in response to injury such as ischemia/reperfusion. Expression of HSP70 in cultured cells inhibits apoptotic cell death indicating that the age-related decline in constitutive and inducible HSP70 expression could be an important factor related to overall organ function and increased sensitivity to injury. The hypothesis that decreased HSP70 expression as a result of aging increases tissue sensitivity to injury will be tested in vivo using hsp70-/- mice as a model for declining HSP70 expression. Two Specific Aims relevant to tissue injury will be carried out: Specific Aim 1 will determine the relationship between liver damage following acetaminophen drug exposure and HSP70 expression; Specific Aim 2 will determine whether the severity or recovery from renal injury after ischemia/reperfusion is dependent on HSP70 expression levels.

描述（由申请人提供）：衰老的特征是生物体在细胞和组织组织水平上越来越无力应对普通和异常的压力。与应激反应减弱同时发生的是基因表达的相关改变，这可能有助于潜在的机制。在体内和体外，其表达量已被证明随着年龄的增长而下降的基因之一是 70 Kd 热休克蛋白 (HSP70)。 HSP70 最初被认为是热疗后合成的主要蛋白质，现在已知它的合成是为了响应包括毒素和药物在内的各种外源应激。 更重要的是，HSP70 在暴露于压力的组织中表达，无论是作为其正常的一部分 生理功能或对缺血/再灌注等损伤的反应。 HSP70 的表达 培养的细胞抑制细胞凋亡，表明与年龄相关的组成型和诱导型 HSP70 表达下降可能是与整体器官功能和对损伤敏感性增加相关的重要因素。 衰老导致 HSP70 表达降低会增加组织对损伤的敏感性这一假设将使用 hsp70-/- 小鼠作为 HSP70 表达降低的模型进行体内测试。将实施与组织损伤相关的两个具体目标： 具体目标 1 将确定对乙酰氨基酚药物暴露后的肝损伤与 HSP70 表达之间的关系；具体目标 2 将确定缺血/再灌注后肾损伤的严重程度或恢复是否取决于 HSP70 表达水平。