Tissue Sensitivity to Stress in The Absence of HSP70

描述（由申请人提供）：衰老的特征是生物体在细胞和组织水平上对普通和特殊应力的反应能力越来越弱。与应激反应减弱相一致的是基因表达的相关改变，这可能有助于潜在的机制。在体内和体外表达已被证明随年龄下降的基因中，有70 Kd热休克蛋白（HSP 70）。最初被鉴定为热疗后合成的主要蛋白质，现在已知HSP 70在响应包括毒素和药物在内的广泛的外源性应激时合成。 更重要的是，HSP 70在暴露于压力的组织中表达，无论是作为其正常组织的一部分，还是作为其正常组织的一部分。 生理功能或响应损伤如缺血/再灌注。hsp 70表达 培养的细胞抑制凋亡性细胞死亡，表明组成型和诱导型HSP 70表达的年龄相关性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。 将使用hsp 70-/-小鼠作为HSP 70表达下降的模型在体内测试由于衰老导致的HSP 70表达下降增加组织对损伤的敏感性的假设。将进行两个与组织损伤相关的具体目标：具体目标1将确定对乙酰氨基酚药物暴露后肝损伤与HSP 70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HSP 70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.