Wnt responsive stem cells in the prostate

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 DESCRIPTION (provided by applicant): The Prostate gland is an accessory reproductive endocrine organ in males, which expels proteolytic solution in the urethra during ejaculation. In humans, the prostate is located immediately below the base of the bladder surrounding the neck region of the urethra, and is associated with many human diseases, including benign prostate hyperplasia (BPH), prostatitis, and malignancies. The high morbidity of these disorders and related complications are a significant burden on our current healthcare system, and will become even greater for our nation in the coming decades due to a rapid increase of the aging population. Despite the intense research efforts that have been made in past decades, the molecular mechanisms underlying these disorders are still poorly understood. Emerging evidence has shown that stem cells are required to maintain and repair tissues throughout ones' lifetime. Recent studies also demonstrate that certain urogenital sinus cells carry out biological properties to commit to prostate cell fate at the embryonic stage of prostate development. The Wnt signaling pathway plays a critical role in development, morphogenesis, and organogenesis. Wnt growth factors activate different intracellular targets through either the "canonical" or the "non-canonical" pathways. The canonical signaling pathways are mainly mediated through ß-catenin. The Wnt/ß-catenin signaling pathway has been shown to be critical in the development of the prostate at the perinatal stage. Genetic interactions between Wnt/ß-catenin and androgen signaling pathways have been identified in the early development of the prostate. Axin2 is a direct transcriptional target of ß-catenin and is upregulated after activation of Wnt signaling. Recent studies have shown that Axin2 positive cells have stem/progenitor cell properties in a variety of mouse tissues. In this new R01 application, we will use the novel mouse models and other "state-of-the-art" experimental approaches to identify the Wnt/ß-catenin responsive stem/progenitor cells in the prostate, which has never been investigated in the field. Three specific aims are proposed here to test our central hypothesis: Wnt/ß-catenin signaling plays a essential role in prostate development and regeneration through its downstream responsive cells, and that aberrant activation of these responsive cells in the prostate directly contribute t prostate pathology. The proposed study seeks to gain innovative information on prostatic stem/progenitor cells, and may lead to new directions and challenges to current paradigms.