Carlise Bethel, Ph.D.
Molecular and Cell Biology 2006
Area of Doctoral Study: Molecular and Cell Biology
Undergraduate Institution: University of Maryland, Baltimore County
Research Advisor: Charles J. Bieberich, Ph.D.
Current: Postdoctoral Fellow, Johns Hopkins University
Description of Research
The prostate gland is one of the most disease-prone organs of the human body. The three major pathological entities that afflict this organ are chronic inflammatory prostatitis, prostate cancer, and benign prostatic hyperplasia (BPH). BPH is the most common benign proliferative disorder found in any internal organ. It is observed in 88% of autopsies performed in males 80 years of age, and symptomatology compatible with BPH is observed in almost half of all men 50 years of age or older. An estimated 379,000 prostatectomies to treat BPH are performed each year in the United States alone. In addition 40,000 men per year die from prostate carcinoma. Despite the enormity of the problem of prostate disease, there is a dearth of information regarding the development of the prostate gland.
The prostate gland develops as the epithelium of the urogenital sinus invades a mass of mesenchyme near the neck of the bladder. The developmental progression from an undifferentiated urogenital sinus epithelial cell to a fully differentiated prostatic epithelial cell most likely involves a cascade of regulatory events. By analogy to other developmental systems, this regulatory cascade must be driven by transcriptional regulatory molecules. Current hypotheses of prostate development suggest the presence of mesenchymal signals that induce epithelial differentiation. However, these hypotheses have not addressed the nature of the transcriptional programs subsequently initiated and maintained in the prostatic epithelium. A new homeobox gene, Nkx-3.1 encodes a homeodomain transcription factor that is expressed during prostate development and in the adult gland. It is proposed to play a pivotal role in prostate morphogenesis and maintenance. We proposed that Nkx-3.1 itself is capable of specifying the fate of prostatic epithelial cells. This hypothesis will be tested by deriving transgenic mice carrying a transgene consisting of Nkx-3.1 under the control of the mouse uroplakin II (UPII) promoter which will direct expression of the urinary tract of transgenic mice. Transgenic founder generation animals will be identified by Southern blot analysis and bred to produce hemizygous F1 offspring. The pattern of expression of the transgene will be determined by a combination of Northern blot, RT-PCR, and in situ hybridization analyses. This study is designed to provide new insights into the molecular basis of normal prostate differentiation, and elucidate possible mechanisms for prostate disease.