ROLE OF MEMBRANE LIPIDS IN HEAT INJURY

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Evidence that membrane structures are (or effect) the targets of hyperthermic damage comes from experiments showing that membrane lipids modulate sensitivity of cells to hyperthermic exposure. The way in which membrane components interact to influence heat damage, however, still requires appreciable clarification. The long term goal of this proposal is to clarify the role played by membrane lipids in heat-induced injury and death of cells and inactivation of viruses and to establish the extent to which hyperthermic damage and the development of thermal tolerance are mediated through effects on (i) lipid metabolism (ii) membrane lipids, including changes in the microenvironment of specific membrane proteins and (iii) specific membrane targets (e.g. proteins). We intend to achieve this long term objective by determining how sensitivity, thermal tolerance, lipid metabolism, viral attachment and entry (i.e. proteins and their lipid microenvironments) are affected in cells which have adapted their lipid membrane composition. The extent to which these several parameters are related in heated cells and viruses will be examined. Further to establish the extent of changes in lipid metabolism and cellular heat sensitivity that occur in virally infected cells and evaluate the importance of the lipid component of the viral envelope in various phases of the virus life cycle (attachment, entry and also assembly, budding and release). We further aim to see whether manipulating the host cell lipid can modify either viral lipids, viral sensitivities to heat or aspects of the viral life cycle and whether changes in either viral lipids or viral sensitivities to heat inactivation are occasioned by viral assembly in thermotolerant host cells. Our findings on the interrelationships between hyperthermia, cellular membranes and the viral life cycle will be translated into the context of an in vivo animal model. In addition to their importance for hyperthermia, the proposed studies have wider implications, being relevant to questions of cellular lipid organization and viral biology. It is anticipated that our studies will provide basic information that will answer questions relevant to the design of clinical protocols using hyperthermia to treat cancer and viral diseases.