The overall goal of this proposal is to develop my technical and professional abilities to become an independent investigator at a top-tier academic institution capable of providing a fully supportive research environment for my pursuit of the molecular links between systemic metabolic stress and chronic urogenital dysfunction. This will be pursued through a scientific project that will determine how systemic metabolic alterations affect local prostatic metabolism and differentiation. I will continue to foster strong interdisciplinary relationships with epidemiologists, diabetologists and molecular biologists to capitalize on the novel models of stromal-epithelial interactions developed in our laboratory. To achieve these goals, I will enroll in research training activities provided by the NIH/MMPC/NIDDK, the Vanderbilt University Medical Center Biomedical Research and Training office and the Vanderbilt Institute for Clinical Training and Research. These include meetings on mouse and experimental models for metabolic research, biostatistics and proteomics analysis. The Vanderbilt Diabetes and Research Training Center also provides funding opportunities, meetings and seminars in conjunction with its Enrichment, Training and Outreach Program. Additional career development mechanisms will include instructive seminars at national meetings on obesity, diabetes and urology, mentored guidance in grant and manuscript preparation, and academic job interviewing. An advisory committee will evaluate the completion of both my scientific and career development milestones and facilitate my transition to an independent investigator. Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are a severe physical and financial burden, which, given their association with aging and metabolic dysfunction, will continue to increase in terms of the number afflicted. Moreover, clinical management of BPH/LUTS has reached limitations in efficacy, predominantly due to a poor understanding of the mechanisms of therapeutic resistance in obese and diabetic patients. Increased focus on the fundamental metabolic mechanisms governing prostatic differentiation and immunomodulation is needed to identify new targets for preventing benign growth and inflammation in obese and diabetic patients. Based on our preliminary studies in mice and humans, I hypothesize that insulin-regulated carbohydrate/fatty acid flux is a key mediator of the differentiation program driven by tissue interactions in prostate and that obesity and type II diabetes disrupt this homeostasis leading to hypertrophy and inflammation.
The specific aims of this study are as follows:
Aim 1 : Determine whether basal cell fatty acid oxidation inhibits luminal epithelial differentiation.
Aim 2 : Determie whether PDK4 ablation or inhibition reduces obesity-induced prostatic hyperplasia and inflammation in vivo.
Aim 3 : Determine whether insulin inhibits prostate fatty acid oxidation in diabetic mice. Based on preliminary data, it is expected that prostate insulin insensitivity increases PDK4 levels and fatty acid flux, leading to hyperplasia, inflammation and resistance to therapy in BPH.
The mechanisms responsible for the development of benign prostatic hyperplasia (BPH) remain unclear despite recent strong epidemiological correlations with obesity and diabetes. Because obese patients are more likely to fail traditional therapy, it i important to identify the molecular links between obesity, diabetes and BPH. It is anticipated that the results of this proposal will provide a molecular rationale for therapeutically targeting systemic or local fatty acid metabolism to reduce prostatic hyperplasia and inflammation in obese and diabetic patients.
|Henry, Gervaise H; Loof, Nicolas; Strand, Douglas W (2017) OMIP-040: Optimized gating of human prostate cellular subpopulations. Cytometry A 91:1147-1149|
|Raj, Ganesh V; Sareddy, Gangadhara Reddy; Ma, Shihong et al. (2017) Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers. Elife 6:|
|McLean, Dalton T; Strand, Douglas W; Ricke, William A (2017) Prostate cancer xenografts and hormone induced prostate carcinogenesis. Differentiation 97:23-32|
|Wang, Zongwei; Hu, Libing; Salari, Keyan et al. (2017) Androgenic to oestrogenic switch in the human adult prostate gland is regulated by epigenetic silencing of steroid 5?-reductase 2. J Pathol 243:457-467|
|Henry, Gervaise; Malewska, Alicia; Mauck, Ryan et al. (2017) Molecular pathogenesis of human prostate basal cell hyperplasia. Prostate 77:1344-1355|
|Strand, Douglas W; Costa, Daniel N; Francis, Franto et al. (2017) Targeting phenotypic heterogeneity in benign prostatic hyperplasia. Differentiation 96:49-61|
|Zhang, Boyu; Kwon, Oh-Joon; Henry, Gervaise et al. (2016) Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor. Mol Cell 63:976-89|
|Austin, David C; Strand, Douglas W; Love, Harold L et al. (2016) NF-?B and androgen receptor variant expression correlate with human BPH progression. Prostate 76:491-511|
|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-?B and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance. Prostate 76:1004-18|
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