Cellular homeostasis and development in vertebrates is controlled by several processes that include cell proliferation, differentiation and cell death (apoptosis). An emerging concept of considerable importance is that the apoptotic program is tightly regulated by cellular genes with effector or repressor function. Within mammals, the first regulatory gene identified is bcl-2, that functions as a repressor of apoptotic cell death. However, bcl-2 falls to block several forms of apoptosis arguing that certain cell deaths are independent of bcl-2. To identify cell death regulatory genes, a functional cloning strategy was developed. We have isolated a novel gene, bcl-x, that functions as a dominant regulator of apoptosis in vertebrates. In humans two forms of bcl-x, bcl-xl and bcl-xs are expressed in tissues. Bcl-xl is a powerful repressor of apoptotic cell death. Remarkably, expression of bcl-xs facilitates cell death by inhibiting the repressor activity of bcl-2. Importantly, our studies show a differential regulation of bcl-xl, bcl-xs and bcl-2 in tissues. Thus, our hypothesis is that bcl-x plays a critical role in modulating pathways of cell death in the animal. The focus of this RCDA proposal is the molecular and functional analysis of bcl-x in the mouse. The immediate plans are: (i) characterize the genomic organization of bcl-x (ii) localize in detail the expression of bcl-xl and bcl-xs during embryonic and postnatal development (iii) identify interactions between bcl-x and cellular proteins and (iv) target bcl-x to lymphoid tissues in a transgenic model to assess bcl-x function in the animal. My long-term career goals are to establish a productive research program m an academic environment. Specifically, l am interested in the understanding of the genetic and biochemical basis of apoptosis so that we can develop strategies to manipulate the apoptotic mechanism in diseases characterized by abnormal patterns of cell death.
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