Tissue Sensitivity to Stress in The Absence of HSP70

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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.