Breast cancer remains the leading cause of cancer death among females, followed by lung cancer, which in males, is the leading cause of cancer death. Resistance to chemotherapy, either as an inherent or as an acquired property of the malignant cell, continues to limit the efficacy of this form of cancer therapy. All cells have a large family of proteins, referred to as heat shock or stress proteins, that act as a cellular defense mechanism by upregulating their expression in response to many forms of stress. Many cancer chemotherapeutic agents act as stressors. It is also clear that these proteins have important functions in the unstressed cell. One member of this family, the serine/threonine phosphoprotein hsp 28, appears to have a role in growth control, differentiation, and In some forms of chemoresistance. Recent evidence indicates a role for hsp 28 in the regulation of actin microfilament integrity. A better understanding of the biochemical function of hsp 28 will likely provide insight into the rearrangements of the cytoskeleton associated with development, differentiation, and malignant transformation. Several complementary methods will be employed to examine the putative interaction between hsp 28 and actin including immunoprecipitation, chemical cross-linking, gel filtration, SDS-PAGE and immunofluorescence. Microinjection of hsp 28 or its corresponding antibody into living cells will be used to manipulate levels of hsp 28. The consequences of such manipulations on the actin cytoskeleton as well as on cellular thermosensitivity, gene expression, the cell cycle and/or the differentiation process will be examined. More efficacious cancer chemotherapeutic strategies may emerge from these studies. Possible strategies for mitigating the effects of acute lung injury may also emerge. The experiments will be done at the Lung Biology Center, a unique environment at San Francisco General Hospital that seeks to integrate basic and clinical aspects of pulmonary medicine. Formal didactic courses in molecular genetics and cell biology as well as several seminar series offered through the Program in Cellular and Molecular Medicine at SFGH, the Cardiovascular Research Institute, and the Program of Excellence in Molecular Biology at UCSF complement and enhance the proposed training program. The proposed training program has been designed to train the applicant to eventually establish his own independent research program within a pulmonary division.
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