研究介紹：炎症與纖維化是糖尿病腎病（DN）的主要特徵。研究發現生長轉化因子TGF-β/Smad信號在糖尿病所致炎症與纖維化中均起重要作用。我們認為TGF-β/Smad信號通路失調是導致糖尿病腎損傷的主要機制，恢復信號通路或有治療價值。為此我們通過以下研究證實：（1）研究Smad7基因在DN中的作用，及評估Smad7基因治療效果；（2）研究miR-29在DN中的作用，及評估miR-29基因治療效果；（3）研究C反應蛋白（CRP）在DN中的作用及機制。 / 研究方法：（1）利用Smad7基因敲除（KO）小鼠建立糖尿病小鼠，並研究Smad7基因在DN的作用，並在链脲佐菌素（STZ）誘導的糖尿病大鼠上利用微泡導入Smad7基因治療觀察其療效；（2）在10週齡db/db小鼠上利用微泡導入可誘導的miR-29b基因，觀察miR-29b在糖尿病腎病中的作用，並用miR-29敲除或高表達細胞株研究其機制；（3）利用CRP轉基因小鼠誘導糖尿病，觀察CRP在DN中的作用，及以高糖和/或CRP刺激腎小管細胞研究CRP的致病機制。 / 研究結果：我們發現（1）糖尿病Smad7 KO小鼠出現更嚴重的腎損傷，包括蛋白尿增加，腎臟炎症及纖維化加重。進一步研究發現Smad7下調所致TGF-β/Smad和NF-kB信號過度活化是導致腎臟炎症及纖維化加重的重要原因。運用基因治療恢復糖尿病大鼠的Smad7水平，發現能夠減輕蛋白尿增加，及抑制TGF-β/Smad引起的纖維化和NF-kB所致炎症反應；（2）我們發現miR-29b在20週齡db/db小鼠比10週齡的顯著降低，並伴隨有蛋白尿加重，腎臟纖維化和炎症反應增加，及TGF-β/Smad，NF-kB，T-bet信號上調，而miR-29b基因治療能減輕蛋白尿，及減輕腎臟纖維化和炎症反應增加，及TGF-β/Smad，NF-kB，T-bet信號上調。體外實驗證實AGEs刺激miR-29敲除細胞株增加纖維化，伴隨有TGF-β/Smad3及炎症因子上調，而刺激高表達細胞株能抑制纖維化，及TGF-β/Smad和炎症因子下調；（3）糖尿病CRP轉基因小鼠出現更嚴重的腎損傷，出現蛋白尿和腎損傷分子-1上升、巨噬細胞和T細胞侵潤、炎症和纖維化增加，並伴有CRP受體（CD32a）上調、TGF-β/Smads及NFκB/p65信號過度活化。體外實驗進一步證實CRP通過其受體CD32a/CD64增加炎症和纖維化。另外證實CRP與高糖有協同作用。 / 結論：TGF-β/Smad信號通路是糖尿病腎病的重要致病機制。糖尿病腎病導致Smad7、miR-29b下調，運用基因治療恢復其表達能減輕糖尿病腎損傷。 / Diabetic nephropathy (DN) is characterized by renal fibrosis and inflammation. Increasing evidence shows that TGF-β/Smad signaling plays a critical role in DN. This thesis tested a hypothesis that TGF-β/Smad signaling may play a central role in diabetic kidney injury and targeting this pathway may represent a novel therapy for DN. The hypothesis was tested in a type-1 model of diabetes induced in Smad7 knockout (KO) or CRP transgene, and the therapeutic potential for DN was examined by overexpressing renal Smad7 or miR-29b in both type-1 or type-2 models of diabetes. / As described in Chapter Three, the protective role and therapeutic potential of Smad7 in diabetic kidney disease was investigated in streptozotocin-induced diabetic model in Smad7 KO mice and in diabetic rats given Smad7 gene transfer using an ultrasound-microbubble-mediated technique. Results showed that Smad7 KO mice developed more severe diabetic kidney injury than wild type (WT) mice as evidenced by a signicant increase in microalbuminuria, renal brosis, and renal inammation, which was mediated by enhanced activation of both TGF-β/Smads and NF-κB signaling pathways. To develop a therapeutic potential for diabetic kidney disease, Smad7 gene was transferred into the kidney, which results in high levels renal Smad7, thereby blocking microalbuminuria, TGF-β/Smad3-mediated renal brosis and NF-κB/p65-driven renal inammation in diabetic rats. / To test a novel hypothesis that TGF-β/Smad3-mediated DN via the Smad3-dependent miR-29, in Chapter Four, the role and mechanisms of miR-29b in DN were examined in vitro in a stable mesangial cell line with overexpression or knockdown of miR-29b and the therapeutic effect of miR-29b on DN was developed by delivering a Dox-inducible miR-29b into 10-week db/db mice. Results showed that addition of AGEs induced a loss of miR-29b with increased fibrosis and inflammation in mesangial cells, which was further enhanced with miR-29b knockdown, but inhibited by overexpressing miR-29b. In db/db mice, reduction of renal miR-29b over the 20 week time was associated with a marked increase in microabluminuria, renal fibrosis and inflammation. Restoring miR-29b resulted in inhibition of kidney injuries by blocking TGF-β/Smad3-mediated renal fibrosis, NF-kB/p65-driven renal inflammation, and importantly, the Th1-dependent immune response, revealing a critical role and therapeutic potential for miR-29b in the pathogenesis of DN. / Finally, diabetic kidney injury was also assessed in under high inflammation conditions in CRP transgenic (Tg) mice. As shown in Chapter Five, CRP Tg mice developed more severe diabetic kidney injury than WT mice, as evidenced by a significant increase in microalbuminuria and kidney injury molecule-1, macrophages and T cells, and upregulation of pro-inflammatory cytokines and extracellular matrix. CRP-mediated DN was associated with upregulation of CRP receptor, CD32a, and over-activation of the TGF-β/Smads and NFκB/p65 signaling pathways. These findings were further confirmed in vitro under high levels of CRP. In addition, CRP was induced by high glucose, which synergistically promoted high glucose-mediated renal inflammation and fibrosis, suggesting a positive feedback-loop between CRP and high glucose under diabetic conditions. / In conclusion, TGF-β/Smads play critical roles in the pathogenesis of DN. Loss of renal Smad7 and miR-29b may be a key mechanism of DN. Thus, over-expression of Smad7 or miR-29b may represent novel therapeutic strategies for diabetic kidney complications. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chen, Haiyong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 202-236). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / ABSTRACT --- p.ii / DECLARATION --- p.vi / ACKNOWLEDGEMENT --- p.vii / PUBLICATIONS --- p.ix / PRESENTATIONS/AWARDS --- p.xi / TABLE OF CONTENTS --- p.xii / LIST OF ABBREVIATIONS --- p.xxii / LIST OF FIGURES/TABLES --- p.xxiv / Chapter CHAPTER ONE --- INTRODUCTION --- p.1 / Chapter 1.1 --- TGF-β superfamily --- p.2 / Chapter 1.2 --- TGF-β/Smad signaling pathway --- p.3 / Chapter 1.2.1 --- TGF-β --- p.3 / Chapter 1.2.1.1 --- TGF-β structure --- p.3 / Chapter 1.2.1.2 --- Activation of latent TGF-β --- p.4 / Chapter 1.2.1.3 --- Latent TGF-β receptors --- p.6 / Chapter 1.2.2 --- TGF-β signaling pathway --- p.7 / Chapter 1.2.2.1 --- Receptors --- p.7 / Chapter 1.2.2.2 --- Smads --- p.10 / Chapter 1.2.2.3 --- Smad-dependent TGF-β signaling pathways --- p.13 / Chapter 1.2.2.4 --- Smad-independent TGF-β signaling pathways --- p.14 / Chapter 1.3 --- Diabetes nephropathy --- p.15 / Chapter 1.3.1 --- Diabetes Mellitus --- p.15 / Chapter 1.3.2 --- Type 1 and type 2 diabetes --- p.16 / Chapter 1.3.3 --- Diabetic complications --- p.16 / Chapter 1.3.4 --- Cellular and molecular mechanisms in diabetic complications --- p.17 / Chapter 1.3.4.1 --- Increased polyol pathway flux --- p.17 / Chapter 1.3.4.2 --- Increased advanced glycation end-products (AGEs) formation --- p.18 / Chapter 1.3.4.3 --- Activation of protein kinase C (PKC) isoforms --- p.20 / Chapter 1.3.4.4 --- Increased hexosamine pathway flux --- p.22 / Chapter 1.3.4.5 --- Increased Reactive Oxygen Species --- p.23 / Chapter 1.3.5 --- Diabetic kidney injuries --- p.24 / Chapter 1.3.5.1 --- Exacerbation of renal structure and function --- p.24 / Chapter 1.3.5.2 --- Fibrosis in diabetic nephropathy --- p.25 / Chapter 1.3.5.3 --- Inflammation in diabetic nephropathy --- p.26 / Chapter 1.4 --- Role of TGF-β/Smad signaling pathway in diabetic nephropathy --- p.28 / Chapter 1.4.1 --- Smad-depedent signaling in diabetic nephropathy --- p.28 / Chapter 1.4.2 --- Cross talk between Smads and other signaling pathways in diabetic nephropathy --- p.30 / Chapter 1.4.3 --- TGF-β/Smads and MicroRNA regulation in diabetic nephropathy --- p.32 / Chapter CHAPTER TWO --- MATERIALS AND METHODS --- p.35 / Chapter 2.1 --- Materials --- p.36 / Chapter 2.1.1 --- Regents and equipment --- p.36 / Chapter 2.1.1.1 --- Reagents and equipment for cell culture --- p.36 / Chapter 2.1.1.2 --- Reagents and equipment for real-time RT-PCR --- p.37 / Chapter 2.1.1.3 --- Reagents and equipment for western blotting --- p.38 / Chapter 2.1.1.4 --- Reagents and equipment for immunohistochemistry --- p.39 / Chapter 2.1.1.5 --- Reagents and equipment for in situ hybridization --- p.40 / Chapter 2.1.1.6 --- Reagents and equipment for plasmid purification --- p.40 / Chapter 2.1.1.7 --- Reagents and equipment for genotyping --- p.41 / Chapter 2.1.1.8 --- Other reagents --- p.41 / Chapter 2.1.2 --- Buffers --- p.42 / Chapter 2.1.2.1 --- Western blotting buffer --- p.42 / Chapter 2.1.2.2 --- Immunohistochemistry buffer --- p.45 / Chapter 2.1.2.3 --- ELISA buffers --- p.47 / Chapter 2.1.2.4 --- In Situ hybridization buffer --- p.48 / Chapter 2.2.2 --- Antibodies --- p.49 / Chapter 2.2.3 --- Primer sequences --- p.49 / Chapter 2.2 --- Methods --- p.56 / Chapter 2.2.1 --- Animal model --- p.56 / Chapter 2.2.1.1 --- Animals --- p.56 / Chapter 2.2.1.2 --- Diabetic animal models --- p.57 / Chapter 2.2.2 --- Sample Collection --- p.59 / Chapter 2.2.2.1 --- Urine collection --- p.59 / Chapter 2.2.2.2 --- Plasma collection --- p.59 / Chapter 2.2.2.3 --- Tissue collection --- p.60 / Chapter 2.2.2.4 --- Paraffin embedding --- p.60 / Chapter 2.2.3 --- Ultrasound-microbubble-mediated gene transfer system --- p.61 / Chapter 2.2.3.1 --- Smad7 gene therapy --- p.61 / Chapter 2.2.3.2 --- miR-29 gene therapy --- p.62 / Chapter 2.2.4 --- Microalbumin and renal function --- p.63 / Chapter 2.2.4.1 --- Microalbuminuria --- p.63 / Chapter 2.2.4.2 --- Creatinine measurement --- p.63 / Chapter 2.2.5 --- Enzyme-Linked Immunosorbent Assay (ELISA) --- p.64 / Chapter 2.2.6 --- Histology and immunohistochemistry --- p.64 / Chapter 2.2.6.1 --- Tissue process --- p.64 / Chapter 2.2.6.2 --- Periodic Acid-Schiff Staining (PAS) --- p.64 / Chapter 2.2.6.3. --- Immunohistochemistry (IHC) --- p.65 / Chapter 2.2.6.4 --- In Situ hybridization --- p.66 / Chapter 2.2.6.5 --- Quantitation of histology and IHC --- p.67 / Chapter 2.2.7 --- Cell culture --- p.67 / Chapter 2.2.8 --- Real-time polymerase chain reaction (PCR) --- p.69 / Chapter 2.2.9 --- Western Blotting --- p.70 / Chapter 2.3 --- Statistical analysis --- p.71 / Chapter CHAPTER THREE --- THE PROTECTIVE ROLE OF SMAD7 IN DIABETIC NEPHROPATHY --- p.72 / Chapter 3.1 --- Introduction --- p.73 / Chapter 3.2 --- Materials and methods --- p.74 / Chapter 3.2.1 --- Animal models --- p.74 / Chapter 3.2.2 --- Ultrasound-mediated gene transfer of inducible Smad7 gene-bearing microbubbles into the kidney --- p.74 / Chapter 3.2.3 --- Real-time PCR --- p.75 / Chapter 3.2.4 --- Western blotting --- p.75 / Chapter 3.2.5 --- Microalbuminuria and urinary creatinine analysis --- p.76 / Chapter 3.2.6 --- Histology and immunohistochemistry --- p.76 / Chapter 3.2.7 --- Statistical analysis --- p.77 / Chapter 3.3 --- Results --- p.77 / Chapter 3.3.1 --- Genotyping for Smad7 KO and WT mice --- p.77 / Chapter 3.3.2 --- Disruption of Smad7 enhances diabetic kidney injury --- p.78 / Chapter 3.3.3 --- Disruption of Smad7 enhanced fibrosis in diabetic kidney --- p.80 / Chapter 3.3.3.1 --- Collagen I is enhanced in diabetic Smad7 KO mice --- p.81 / Chapter 3.3.3.2 --- Collagen IV is enhanced in diabetic Smad7 KO mice --- p.82 / Chapter 3.3.3.3 --- Fibronectin is enhanced in diabetic Smad7 KO mice --- p.84 / Chapter 3.3.4 --- Disruption of Smad7 exacerbates inflammation in diabetic kidney --- p.85 / Chapter 3.3.4.1 --- Disruption of Smad7 increases IL-1β in diabetic kidney --- p.85 / Chapter 3.3.4.2 --- Disruption of Smad7 increases TNF-α in diabetic kidney --- p.86 / Chapter 3.3.4.3 --- Disruption of Smad7 Increases MCP-1 in diabetic kidney --- p.87 / Chapter 3.3.4.4 --- Disruption of Smad7 increases ICAM-1 in diabetic kidney --- p.88 / Chapter 3.3.4.5 --- Disruption of Smad7 increases macrophage infiltration in diabetic kidney --- p.90 / Chapter 3.3.5 --- Enhanced activation of TGF-β/Smad3 and NF-κB Signaling is a central mechanism by which disruption of Smad7 promotes diabetic renal fibrosis and inflammation --- p.91 / Chapter 3.3.5.1 --- Smad7 decreases in diabetic kidney --- p.91 / Chapter 3.3.5.2 --- Enhanced activation of TGF-β/Smad3 signaling pathway contributes to fibrosis in diabetic kidney --- p.92 / Chapter 3.3.5.3 --- Enhanced activation of NF-κB/p65 signaling pathway contributes to inflammation in diabetic kidney --- p.93 / Chapter 3.3.6 --- Smad7 transfection rate by gene therapy in diabetic rats --- p.94 / Chapter 3.3.7 --- Restoring Smad7 attenuates kidney injury in diabetic rats --- p.96 / Chapter 3.3.8 --- Restoring Smad7 attenuates renal fibrosis in diabetic rats --- p.98 / Chapter 3.3.8.1 --- Restoring Smad7 attenuates collagen I in diabetic kidney --- p.98 / Chapter 3.3.8.2 --- Restoring Smad7 attenuates collagen IV in diabetic kidney --- p.100 / Chapter 3.3.8.3 --- Restoring Smad7 attenuates collagen III in diabetic kidney --- p.101 / Chapter 3.3.9 --- Restoring Smad7 attenuates renal inflammation in diabetic rats --- p.104 / Chapter 3.3.9.1 --- Restoring Smad7 attenuates IL-1b in diabetic kidney --- p.104 / Chapter 3.3.9.2 --- Restoring Smad7 attenuates TNF-α in diabetic kidney --- p.106 / Chapter 3.3.9.3 --- Restoring Smad7 Attenuates MCP-1 in diabetic kidney --- p.107 / Chapter 3.3.9.4 --- Restoring Smad7 attenuates ICAM-1 in diabetic kidney --- p.109 / Chapter 3.3.9.5 --- Restoring Smad7 attenuates macrophage infiltration in diabetic kidney --- p.111 / Chapter 3.3.10 --- Blockade of activation of TGF-β/Smad3 and NF-κB signaling is a key mechanism by which overexpression of smad7 inhibits diabetic renal injury --- p.113 / Chapter 3.3.10.1 --- Restoring Smad7 inhibits activation of TGF-β/Smad3 signaling --- p.113 / Chapter 3.3.10.2 --- Restoring Smad7 inhibits activation of NF-κB signaling --- p.115 / Chapter 3.3 --- Discussion --- p.117 / Chapter CHAPTER FOUR --- THE PROTECTIVE ROLE OF MICRORNA-29B IN DIABETIC NEPHROPATHY --- p.121 / Chapter 4.1 --- Introduction --- p.122 / Chapter 4.2 --- Materials and methods --- p.123 / Chapter 4.2.1 --- Animal model --- p.123 / Chapter 4.2.2 --- Ultrasound-microbubble-mediated-miR-29 gene transfer --- p.124 / Chapter 4.2.3 --- Real-time polymerase chain reaction (PCR) --- p.124 / Chapter 4.2.4 --- Western Blotting --- p.125 / Chapter 4.2.5 --- Albumin excretion measurement --- p.126 / Chapter 4.2.6 --- ELISA --- p.126 / Chapter 4.2.7 --- Histology and immunohistochemistry --- p.126 / Chapter 4.2.8 --- In Situ hybridization --- p.127 / Chapter 4.2.9 --- Cell culture --- p.128 / Chapter 4.2.10 --- Statistical analysis --- p.129 / Chapter 4.3 --- Results --- p.129 / Chapter 4.3.1 --- Over-expression of miR-29b attenuates, but knockdown of miR-29b enhances fibrosis in vitro --- p.129 / Chapter 4.3.1.1 --- Over-expression of miR-29b attenuates fibrosis --- p.129 / Chapter 4.3.1.2 --- Knockdown of miR-29b enhances fibrosis --- p.132 / Chapter 4.3.2 --- Restoring miR-29b attenuates kidney injury in db/db mice --- p.134 / Chapter 4.3.3 --- Restoring miR-29b attenuates renal fibrosis in db/db mice --- p.139 / Chapter 4.3.3.1 --- Restoring miR-29b attenuates collagen IV in db/db mice --- p.139 / Chapter 4.3.3.2 --- Restoring miR-29b attenuates collagen I in db/db mice --- p.141 / Chapter 4.3.3.3 --- Restoring miR-29b attenuates fibronectin in db/db mice --- p.144 / Chapter 4.3.4 --- Restoring miR-29b inhibits renal fibrosis via TGF-β/Smad3 dependent pathway --- p.146 / Chapter 4.3.5 --- Restoring miR-29b inhibits th1 immune response in diabetic kidney --- p.148 / Chapter 4.3.6 --- Restoring miR-29b inhibits inflammation in diabetic kidney --- p.151 / Chapter 4.4 --- Discussion --- p.154 / Chapter 4.5 --- Conclusion --- p.161 / Chapter CHAPTER FIVE --- THE PATHOGENIC ROLE OF C-REACTIVE PROTEIN IN DIABETIC NEPHROPATHY --- p.162 / Chapter 5.1 --- Introduction --- p.163 / Chapter 5.2 --- Materials and methods --- p.164 / Chapter 5.2.1 --- Mouse model of STZ induced diabetes --- p.164 / Chapter 5.2.2 --- Measurement of blood glucose, urinary albumin excretion, and creatinine clearance --- p.165 / Chapter 5.2.3 --- Histology and immunohistochemistry --- p.165 / Chapter 5.2.4 --- Cell culture --- p.166 / Chapter 5.2.5 --- Real-time PCR --- p.166 / Chapter 5.2.6 --- Western blotting --- p.167 / Chapter 5.2.7 --- Statistical analyses --- p.168 / Chapter 5.3 --- Results --- p.168 / Chapter 5.3.1 --- Diabetic renal injury is exacerbated in CRP Tg mice --- p.168 / Chapter 5.3.2 --- Renal inflammation is exacerbated in diabetic CRP Tg mice --- p.172 / Chapter 5.3.2.1 --- F4/80+ macrophage infiltration is enhanced in diabetic CRP Tg mice --- p.172 / Chapter 5.3.2.2 --- CD3+ T cell infiltration is enhanced in diabetic CRP Tg mice --- p.173 / Chapter 5.3.2.3 --- TNF-α expression is enhanced in diabetic CRP Tg mice --- p.173 / Chapter 5.3.2.4 --- IL-1β expression is enhanced in diabetic CRP Tg mice --- p.174 / Chapter 5.3.3 --- Renal fibrosis is enhanced in diabetic CRP Tg mice --- p.175 / Chapter 5.3.3.1 --- Collagen I is enhanced in Diabetic CRP Tg mice --- p.175 / Chapter 5.3.3.2 --- Collagen IV is enhanced in diabetic CRP Tg mice --- p.176 / Chapter 5.3.4 --- Enhanced CRP signaling and activation of NF-κB and TGF-β/Smad3 signaling are key mechanism by which CRP promotes diabetic renal injury --- p.177 / Chapter 5.3.4.1 --- Enhanced CRP signaling via upregulation of CD32a expression --- p.177 / Chapter 5.3.4.2 --- enhanced activation of NF-κB signaling is key mechanism by which CRP promotes renal inflammation --- p.179 / Chapter 5.3.4.3 --- Enhanced activation of TGF-β/Smad3 signaling is key mechanism by which CRP promotes renal inflammation --- p.181 / Chapter 5.4 --- Discussion --- p.194 / Chapter 5.5 --- Conclusion --- p.197 / Chapter CHAPTER SIX --- SUMMARY AND CONCLUSION --- p.198 / REFERENCES --- p.202

"June 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 162-187). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

In order to further investigate the functions of ERRbeta/gamma in prostate cancer, the following aspects were explored in my study. My results show that: (1) Expressions of ERRbeta/gamma was down-regulated in prostate cancer cell lines and prostate cancer tissues. And only the short-form but not other ERRbeta isoforms was expressed in prostatic cells. (2) Overexpression of ERRbeta/gamma significantly inhibited the cell proliferation in vivo and in vitro. (3) Cell cycle analysis showed that S-phase fraction of ERRbeta/gamma stable clones was significantly decreased, while there was no significantly induced apoptosis by ERRbeta/gamma overexpression. This was confirmed by BrdU incorporation assay. (4) Expressions of two cyclin-CDK inhibitors p21Cip1/Waf1 and p27Kip1 were increased significantly in ERRgamma clones, but only p21 in ERRbeta clones. (5) P21 and p27 gene promoters could be transactived by ERRgamma, but only p21 by ERRbeta. The transactivity of p21 by ERRbeta can be potently enhanced by PGC-1alpha (6) Deletion mutants of ERRgamma showed the transaction of p21 required an intact DNA-binding domain. (7) DY131, the ERRbeta/gamma agonist, further potentiated the growth inhibition in ERRbeta/gamma-stable clones in a dose-dependent manner. (8) There were increase in number of giant potential-active mitochondria and accumulation of lipid droplets in ERRbeta-clones. / Prostate cancer is the most common diagnosed cancers in men in western countries. Despite the substantial clinical significance, the mechanisms underlying the development and progression of prostate cancer are poorly understood. ERRs(alpha, beta, gamma) belong to orphan nuclear. All ERR subtypes share significant homology with estrogen receptors (ERs) in their protein structures. Functionally ERRalpha shares, regulates same target genes with ERalpha and is involved in carcinogenesis, while the ERRbeta and ERRgamma are still unknown. / The results obtained indicate that ERRbeta/gamma inhibit proliferation of prostate cancer cells by arresting of cell cycle progression, suggesting a tumor suppressor function for ERRbeta/gamma in prostate cancer. p21 may be the key mediator of this suppressor function, and the p21 is the target gene of ERRbeta/gamma. The selective ERRbeta/gamma agonist, DY131, potently inhibited the proliferation of ERRbeta/gamma-positive prostate cancer cells, suggesting ERRbeta and gamma could be a potential therapeutic target for prostate cancer therapy. / Yu, Shan. / "July 2007." / Adviser: Franky L. Chan. / Source: Dissertation Abstracts International, Volume: 69-01, Section: B, page: 0238. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 140-165). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Tsang Suk Ying. / "August 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 196-226). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Thesis (M.D) -- University of Texas Southwestern Medical Center at Dallas, 2007. / Vita. Bibliography: pp. 35-37.

Thesis (Ph. D.)--University of Missouri--Columbia, 2001. / Typescript. Vita. Includes bibliographical references (leaves 326-347). Also available on the Internet.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 103-131).

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 93-113).

Nuclear receptors play crucial roles in the transcriptional regulation of many biological processes such as development and cellular differentiation. ERRalpha is known, along with coactivator PGC-1alpha, to playa central role in the control of energy metabolism in cardiac and skeletal muscle. They activate the expression of many genes involved in mitochondrial oxidative metabolism. Here we identified PROX1, a factor that was previously shown to broadly influence metabolism, as a regulator of this pathway. Indeed, PROX1 interacts in vitro and in vivo with both ERRalpha and PGC-1alpha. To provide more insight on the hepatic functions of ERRalpha and PROX1, we performed ChIP-on-chip using mouse liver, identifying a large number of ERRalpha and PROX1 genomic targets and reinforcing their role in energy metabolism. Over 40% of the target genes were found to be common to both factors and we observed that PROX1 could be recruited to ERRalpha binding sites and act as a negative regulator o fthe ERRalpha/POC-1alpha pathway.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.