Determining the contribution of Sox2 to prostate stem cell activity and benign prostate hyperplasia

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Abstract: The adult human prostate is normally quiescent and does not produce new tissue at an appreciable rate. When this state of quiescence is broken, the prostate epithelium undergoes hyperplastic growth in a chronic condition referred to as benign prostatic hyperplasia. Although hyperplastic growth of the prostate is a common ailment, little is known about the specific epithelial stem cell populations that are thought to contribute to the disease. Prostate epithelial stem cells are marked by multipotency, self-renewal, and tissue regeneration as well as a unique independence of androgen signaling not seen in differentiated prostate epithelial cells. Data from the mentor’s lab shows that the transcription factor Sox2 is expressed during prostate development as well as in a rare population of cells in the adult prostate. Genetic lineage tracing data show that Sox2+ cells persist in the absence of androgen signaling and contribute to new epithelial tissue during prostate regeneration. Although these data imply that Sox2+ cells are epithelial stem cells, a direct experimental approach must be used to define their place in the lineage hierarchy of the prostate as well as the genetic program employed by Sox2 to yield this phenotype. A deeper understanding of the identity and underlying mechanisms of stem cell populations within the prostate epithelium is necessary for the development of improved treatments for prostatic hyperplasia targeting stem cell populations. The scientific objective of this application is to establish the contribution of Sox2 to prostate regeneration. This proposal is innovative because it will be the first to test the necessity of Sox2 in the process of prostate regeneration, as well as being one of the first to catalog the single-cell transcriptomes of a castrate and intact prostate simultaneously for direct comparison. This proposal is significant because it will establish the role of a known stem cell factor in the hierarchy and processes of the prostate epithelium. This will allow for the new therapeutic targets in the effort to create improved treatment regimens for benign prostatic hyperplasia.