The molecular machinery that governs circadian rhythmicity is comprised of transcriptional translational feedback loop whereby clock1 gene products inhibit their own transcription. Experimental manipulation of rhythms by brain lesions altered lighting environments and timed nutritional restriction can affect tumor growth and survival times in laboratory rodent models. It has been shown that aberrant circadian rhythmicity correlates with an increased risk of cancer development and with decreased survival statistics in diagnosed cancer patients. ? ? Using newly developed bioluminescent mouse tumor models, bioluminescent prostate cancer cell lines, ? and newly-developed in vivo molecular imaging techniques, we propose to illustrate the spatiotemporal ? dynamics of circadian rhythms of gene expression in healthy prostate and prostate cancer. We will also ? examine whether temporally restricted nutrition regulates prostate rhythmicity, and tumorigenesis and ? progression. ? ? Specific Aim 1: To evaluate whether prostate cancers have altered circadian rhythms of gene expression compared with healthy prostate tissue via in vitro and in vivo tracking of bioluminescent reporter genes. We will generate a dual transgenic mouse that develops prostate cancer and expresses the Per2: luciferase fusion protein and characterize the mPer2 gene temporal expression profile in prostate intraepithelial neoplasia (PIN), prostate adenocarcinoma, and metastatic foci and in healthy surrounding tissue. In parallel, we will develop a tumorigenic prostate cancer cell line, syngeneic on C57BL/6, which expresses circadian luciferase reporter genes to allow for in vivo tracking of tumor growth and molecular rhythms in tumors in anesthetized mice, and eventually in awake, behaving mice. ? ? Specific Aim 2: To test the hypothesis that nutritional manipulations of circadian rhythms differentially ? affect tumor development We will expose the dual transgenic mice or their WT littermates with bioluminescent tumors to nutritional manipulations known to alter molecular and physiological rhythmicity in peripheral organs: daytime restricted feeding, nighttime restricted feeding, and, as a control, caloric restriction without circadian entrainment. Tumor development and progression will be assessed longitudinally in mouse via in vivo imaging of tumor volume. In parallel, we will assess the effects of each circadian manipulation on circadian clock gene expression patterns in various stages of primary prostate cancer, in healthy prostate gland and in subcutaneous bioluminescent prostate adenocarcinoma cells. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory Grants (P20)
Project #
5P20CA132388-02
Application #
7502659
Study Section
Special Emphasis Panel (ZCA1-SRRB-Y (O1))
Program Officer
Ogunbiyi, Peter
Project Start
2007-09-29
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$134,903
Indirect Cost
Name
Emory University
Department
Urology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Li, Guang; Wei, Jie; Kadbi, Mo et al. (2017) Novel Super-Resolution Approach to Time-Resolved Volumetric 4-Dimensional Magnetic Resonance Imaging With High Spatiotemporal Resolution for Multi-Breathing Cycle Motion Assessment. Int J Radiat Oncol Biol Phys 98:454-462
Wang, Ruoxiang; Sun, Xiaojuan; Wang, Christopher Y et al. (2012) Spontaneous cancer-stromal cell fusion as a mechanism of prostate cancer androgen-independent progression. PLoS One 7:e42653
Zhau, Haiyen E; He, Hui; Wang, Christopher Y et al. (2011) Human prostate cancer harbors the stem cell properties of bone marrow mesenchymal stem cells. Clin Cancer Res 17:2159-69
He, Hui; Davidson, Alec J; Wu, Daqing et al. (2010) Phorbol ester phorbol-12-myristate-13-acetate induces epithelial to mesenchymal transition in human prostate cancer ARCaPE cells. Prostate 70:1119-26
Sun, Xiaojuan; He, Hui; Xie, Zhihui et al. (2010) Matched pairs of human prostate stromal cells display differential tropic effects on LNCaP prostate cancer cells. In Vitro Cell Dev Biol Anim 46:538-46
Thalmann, George N; Rhee, Hong; Sikes, Robert A et al. (2010) Human prostate fibroblasts induce growth and confer castration resistance and metastatic potential in LNCaP Cells. Eur Urol 58:162-71
He, Hui; Xu, Jianchun; Nelson, Peter S et al. (2010) Differential expression of the alpha2 chain of the interleukin-13 receptor in metastatic human prostate cancer ARCaPM cells. Prostate 70:993-1001
He, Hui; Yang, Xiaojian; Davidson, Alec J et al. (2010) Progressive epithelial to mesenchymal transitions in ARCaP E prostate cancer cells during xenograft tumor formation and metastasis. Prostate 70:518-28
Wang, Ruoxiang; He, Hui; Sun, Xiaojuan et al. (2009) Transcription variants of the prostate-specific PrLZ gene and their interaction with 14-3-3 proteins. Biochem Biophys Res Commun 389:455-60
Odero-Marah, Valerie A; Wang, Ruoxiang; Chu, Gina et al. (2008) Receptor activator of NF-kappaB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells. Cell Res 18:858-70