Cunyu Wang
University Of California Los Angeles
Project start date: 2004-04-01
Project end date: 2015-02-28
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Grants awarded to Cunyu Wang
Molecular Regulation Of Human Dental Stem Cell Property
Cunyu Wang, Professor
Oral Biology And Medicineuniversity Of California Los Angeles
Grant 5R01DE016513-06 from National Institute Of Dental & Craniofacial Research IRG: ZDE1
Abstract: The long-time objective of this application is to understand the molecular biology of human postnatal stem cells from dental and periodontal tissues. Recently, human postnatal dental pulp stem cells (DPSCs) have been identified from dental pulp tissues. These cells are multipotent and can generate dentin/pulp-like complexes in vivo. Our exciting preliminary studies presented in this application also discovered that human periodontal ligament (PDL) contains unique stem cells (periodontal ligament stem cells; PDLSCs) which can generate a distinct cementum/PDL-like structure. These human postnatal dental and periodontal stem cells offer an attractive regenerative therapy for dental and periodontal defects caused by dental decay/pulpitisand periodontitis. However, before pushing them into clinical application, it is critical to develop optimal conditions to maintain their sternness during ex vivo expansion and to elucidate molecular mechanisms which control their differentiation and self-renewal. Like bone marrow mesenchymal stem cells (MSCs), these human postnatal dental stem cells appear to be from mesenchymal origin according to their surface markers. During in vitro culture, we also found that these stem cells, similar to MSCs, progressively lost their sternness. Based on our novel findings on the maintenance of MSCs´ function by telomerase, in this application, we will examine whether over-expression of telomerases help to maintain human postnatal dental stem cell properties in vitro and whether Wnt growth factors stimulate telomerase activity and modulate their properties. Moreover, our preliminary studies suggest that Wnt signaling may negatively regulate the activation of NF-icB, a master transcription factor of inflammatory responses, and that NF-KB activated by inflammatory mediators such as TNF inhibit differentiation. Therefore, in this application, we will also explore whether Wnt signaling attenuates the inhibition of human dental stem cell differentiation by TNF. In the realm of therapeutic regeneration for dental and periodontal tissues, due to infection of oral pathogens, the repairing sites are frequently inflamed. Thus, our studies are highly clinically-relevant. Collectively, novel findings from our application will provide a molecular basis for maintaining and regulating human postnatal dental stem cell properties in vitro and in vivo, and have important implications in the regenerative dental medicine
Project start date: 2005-05-01
Project end date: 2010-04-30
NF-kB Signaling In Osteoclastogenesis And Osteolytic Bone Metastasis
Cunyu Wang, Professor
Oral Biology And Medicineuniversity Of California Los Angeles
Grant 1R01CA132134-01A2 from National Cancer Institute IRG: ZRG1
Abstract: The long-term objectives of this application are to understand the molecular mechanisms which control breast cancer bone metastasis. Breast cancer frequently metastasizes to bone in patients with advanced diseases. In contrast to prostate cancer which forms osteoblastic lesion, bone metastasis of breast cancer typically leads to osteolysis which is often accompanied with severe pain, pathological fracture, and hypercalcaemia. Although the molecular mechanism underlying the preferential bone metastasis is yet to be elucidated, it is believed that osteoclasts activated by breast cancer cells, but not breast cancer cells themselves, mediate osteolysis. Osteoclasts play an initiating and pivotal role in stimulating bone-metastatic tumor growth in the marrow cavity. While bone microenvironments allow circulating breast cancer cells to preferentially survive and grow, bone-seeking breast cancer cells may have intrinsic properties to promote osteoclast formation and activation. The central hypothesis of this application is that constitutive nuclear factor-kappa B (NF-?B) activities in breast cancer cells play an integral role in osteolytic bone metastasis and osteoclastogenesis. NF-?B is an inflammatory transcription factor which regulates a broad range of gene expression, including pro-inflammatory cytokines, chemokines and cell adhesion molecules. Using in vitro and in vivo model systems, we have found that constitutive NF-?B activities in breast cancer cells promote osteolytic tumor growth by stimulating osteoclastogenesis. In this application, based on our exciting preliminary studies, we will explore how NF-?B is disregulated and recruited to chromatin to stimulate target gene transcription in breast cancer cells using a combination of biochemical and genetic approaches. We will determine whether NF-?B-induced genes such as chemokines secreted by breast cancer cells stimulate osteoclast formation, thereby promoting osteolytic bone metastasis. Intriguingly, NF-?B is also essential for osteoclastogenesis, and pro-inflammatory cytokines and chemokines have been found to promote osteoclast differentiation by activating NF-?B. However, unlike cytokines, little is known about how chemokines activate NF-?B. Therefore, we will also explore how chemokines trigger an intracellular signaling cascade to activate NF-?B to promote osteoclast differentiation. Taken together, the results from this application will provide novel insights into osteolytic bone metastasis and osteoclast activation by NF-?B, and help to develop new strategies for treating skeletal bone metastasis. The long-objectives of this application are to understand why breast cancer frequently spreads to bone and cause bone destruction. Advanced breast cancer patients with bone metastasis are often incurable and possess severe medical complications. In this application, we will attack this challenging issue from both mechanistic and therapeutic aspects. Based on our recent findings on the promotion of bone metastasis by the transcription factor nuclear factor-kappa B (NF-?B), we will examine whether NF-?B- induced chemokines in breast cancer cells promotes bone metastasis by inducing osteoclast (bone resorbing cells) formation. We will explore how NF-?B activities are regulated in breast cancer cells. New findings from our studies will help us to develop novel strategies for treating bone metastasis by inhibiting NF-?B
Project start date: 2009-02-10
Project end date: 2014-01-31
Cunyu Wang
University Of California Los Angeles
Project start date: 2009-02-10
Project end date: 2014-01-31
Inhibition Of Bone Formation By TNF/NF-kappa B Signaling
Cunyu Wang, Professor
Oral Biology And Medicineuniversity Of California Los Angeles
Grant 5R01DE017684-02 from National Institute Of Dental & Craniofacial Research IRG: SBSR
Project start date: 2008-02-20
Project end date: 2012-01-31
PS-341-induced Apoptosis In Squamous Cell Carcinoma
Cunyu Wang, Professor
Oral Biology And Medicineuniversity Of California Los Angeles
Grant 5R37DE013848-10 from National Institute Of Dental & Craniofacial Research IRG: ZRG1
Project start date: 2000-02-01
Project end date: 2011-03-31
Regulation Of Oncogenesis And Apoptosis By Wnt
Cunyu Wang
Biologic And Materials Sciencesuniversity Of Michigan At Ann Arbor
5R01CA100849-04 (2007): $267657
PS-341-induced Apoptosis In Squamous Cell Carcinoma
Cunyu Wang
University Of Michigan At Ann Arbor
2R01DE013848-06A1 (2006): $329752