Tissue Sensitivity to Stress in The Absence of HSP70

描述(由申请人提供)：衰老的特征是有机体在细胞和组织水平上越来越不能对正常和异常的压力做出反应。与压力反应减弱相一致的是基因表达的相关变化，这可能有助于潜在的机制。在体内和体外表达随年龄增长而下降的基因中，有一种是70kD的热休克蛋白(HSP70)。HSP70最初被认为是热疗后合成的主要蛋白质，现在已知它是在包括毒素和药物在内的广泛的外源压力下合成的。更重要的是，HSP70在暴露于压力下的组织中表达，无论是作为正常组织的一部分 生理功能或对损伤的反应，如缺血/再灌流。热休克蛋白70在卵巢癌组织中的表达 培养的细胞可抑制细胞的凋亡，提示与年龄相关的结构性和诱导性HSP70表达的下降可能是与整体器官功能和损伤敏感性增加有关的一个重要因素。由于衰老导致HSP70表达减少会增加组织对损伤的敏感性这一假说将在体内用HSP70-/-小鼠作为HSP70表达下降的模型进行验证。与组织损伤相关的两个特定目标将被实施：特定目标1将确定对乙酰氨基酚药物暴露后的肝损伤与HSP70表达的关系；特定目标2将确定缺血/再灌注后肾损伤的严重程度或恢复取决于HSP70的表达水平。

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.