Our overall approach is brings together a multidisciplinary team to determine the role of obesity in the development of benign prostatic hyperplasia (BPH). The research team has expertise in biological modeling of urogenital tract disease, epidemiology, and medicine, with special emphasis on model development and clinical manifestations of obesity, infiammation, and metabolic stress. The overall hypothesis is that benign hyperplastic growth of the prostate and associated infiammatory responses are influenced by obesity and diet. We further hypothesize that some of these changes may be reversed by appropriate dietary or surgical intervenfions, while others may become fixed. The project is broken into three aims, all centered on the links between BPH, infiammafion, and obesity.
The first aim will test prostafic histopathologic changes, immune/inflammatory cell recruitment and systemic inflammatory marker changes induced in wild type, lepfin receptor knockout (ob/ob) and low density lipoprotein receptor knockout (LDLR-/-) C57/BL6 mice by high fat/high sucrose or high fat/high corn starch dietary regimens. Our preliminary data demonstrate that these models undergo prostatic changes consistent with aspects of human BPH.
The second aim will examine the reversibility of these phenotypic and infiammatory changes using caloric restriction and Roux-en-Y gastric bypass (RYGB) surgery. These techniques will be applied to the mouse models at specific fimes in the development of inflammation and hyperplasia to determine which aspects of the disease process can be reversed by altering dietary habits.
The third aim will take advantage of a NIDDK supported, prospective epidemiologic study of men with BPH (the Nashville Men's Health Study) to determine if blood and urine biomarkers of obesity and infiammafion and insulin expression and sensifivity are associated with levels of prostate tissue inflammation or BPH symptom progression over time. Speciflc Aims one and two are designed to determine the role of obesity in the induction and maintenance of specific markers of prostatic hyperplasia.
Aim three extends these concepts to obesity, prostate tissue infiammation, and BPH progression in humans. The integrafion of these aims across mouse models and human epidemiology with overlapping biomarker panels will ground the mouse models to the clinical realifies of human BPH, while also developing an understanding of the mechanisms underiying disease pathogenesis.
BPH is a common and debilitating condition often associated with obesity or metabolic dysregulation. Research models needed to study links between obesity and BPH in mice and humans are underdeveloped. This project will generate and fully characterize new mouse models of BPH relevant to obesity and validate and test these against human disease.
|Grabowska, Magdalena M; Kelly, Stephen M; Reese, Amy L et al. (2016) Nfib Regulates Transcriptional Networks That Control the Development of Prostatic Hyperplasia. Endocrinology 157:1094-109|
|Austin, David C; Strand, Douglas W; Love, Harold L et al. (2016) NF-ÎºB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance. Prostate 76:1004-18|
|Austin, David C; Strand, Douglas W; Love, Harold L et al. (2016) NF-ÎºB and androgen receptor variant expression correlate with human BPH progression. Prostate 76:491-511|
|Lin-Tsai, Opal; Clark, Peter E; Miller, Nicole L et al. (2014) Surgical intervention for symptomatic benign prostatic hyperplasia is correlated with expression of the AP-1 transcription factor network. Prostate 74:669-79|