2007 — 2011 |
Kim, Reuben Han-Kyu |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Combined Effect On Hiv and Hpv in Oral Cancer @ University of California Los Angeles
[unreadable] DESCRIPTION (provided by applicant): There is emerging evidence to suggest the direct oncogenic potential of human immunodeficiency virus (HIV) through its trans-activator (Tat) protein. Tat targets the "gate keepers" of mammalian genome, i.e., p53and RB2/p130 tumor suppressors, and may challenge genetic stability by impairing DMA repair activities. Tat may also mediate the interactions of HIV with other oncogenic viruses, such as human papilloma virus (HPV).Tat is released from HIV-infected cells and is capable of penetrating into the target cells, including those harboring HPV DMA. Frequent infection with HPV in the oral cavity has been noted in immunocompromised children and adults infected with HIV. HIV+ patients are more susceptible to infection with multiple HPV subtypes, including types 16 and 18. These "high risk" HPVs are closely associated with development of malignant oral cancer. However, HPV infection alone is not sufficient for tumorigenic cell transformation, which requires additional oncogenic stimuli. Importantly, Tat positively regulates the HPV long control region (LCR) to elevate the expression of E6 and E7 viral oncogenes. Therefore, HIV may enhance the tumorigenic potential of HPV, possibly through Tat. [unreadable] [unreadable] Our long-range goal is to elucidate the role of HIV Tat in the malignant conversion of human oral keratinocytes harboring "high risk" HPV genome. [unreadable] [unreadable] The central hypothesis of this project is that HIV Tat enhances the tumorigenicity of HPV in HOKs. We will test this hypothesis through the following Specific Aims: (1) to investigate the effects of HIV Tat on phenotypic alteration, i.e., proliferation, differentiation, senescence, and apoptosis, of NHOK and HOK harboring HPV genome, (2) to determine the effects of HIV Tat on immortalization and tumorigenic potential of NHOK and HOK harboring HPV genome, (3) to identify the cellular genes and proteins differentially expressed by HIV Tat transduction in NHOK and HOK harboring HPV genome. These studies will ultimately lead us to develop a novel mode for early diagnosis and treatment of HPV-related oral lesions in HIV+ patients. [unreadable] [unreadable] There is emerging evidence to suggest that Tat protein, one of gene products from human immunodeficiency virus (HIV), plays important role in the development of cancer in HIV+ patients. In this study, we will examine the role of Tat protein in the development of cancers, particularly human papilloma virus (HPV)-related cancer in oral tissue. [unreadable] [unreadable] [unreadable]
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2010 — 2011 |
Kim, Reuben Han-Kyu |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Role of Oral Mucosa in Bisphosphonate Related Osteonecrosis of the Jaw @ University of California Los Angeles
DESCRIPTION (provided by applicant): Bisphosphonate (BPs) are potent anti-resorptive agents that are widely used to treat osteoporosis and metastatic bone diseases. Long-term users of BPs are at the higher risk of developing osteonecrosis of the jaw (ONJ). The etiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is thought to be due to its inhibitory effects on osteoclasts, bone resorbing cells important for bone remodeling and healing. However, this alone is insufficient to explain the pathophysiology of BRONJ because wound healing in oral environment is a multi-factorial and complex process that requires orchestrated efforts of different cell types including oral mucosal cells. BRONJ commonly occurs at the site of previous tooth extraction or other surgical interventions and is clinically defined as exposed necrotic bone with unhealed and open oral mucosa. Nonetheless, the exact role of oral mucosa in the pathophysiology of BRONJ is not fully understood. To better understand effects of BPs on oral mucosal cells, we established a 3 dimensional (3D) oral mucosal wound healing model and found that BPs drastically inhibit proliferation and migration of keratinocytes. Similar to this ex vivo model, our in vitro studies also showed the marked inhibition of proliferation and migration by BPs specific to primary normal human oral keratinocytes (NHOK). Our recently developed animal model which recapitulates BA-ONJ also revealed the impaired wound closure with underlying exposed and necrotic bone. Based on our preliminary data, we hypothesize that BP directly impairs reepithelialization (e.g., proliferation and migration) of oral mucosa by targeting the mevalonate pathway. To this end, we propose 1) to examine roles of farnesyl pyrophosphate synthase (FPPS) and RhoA in BP-treated NHOK in vitro and ex vivo, and 2) to examine spatial expression patterns of wound healing-associated proteins in vivo using animal model. The clinical outcomes and benefits outweigh the adverse effects of using BPs. Therefore, BPs will continually be used to manage osteoporosis and metastatic bone diseases, and proper treatment and prevention of BRONJ will remain important and relevant clinical issues in dental and medical practices. Our proposal will provide possible explanations as to why BRONJ occurs in oral-cavity specific manner, and will establish a basis for the future clinical applications in managing and treating BRONJ. Successful completions of the current project will likely lead to R01 grant mechanism focusing on the application of findings to the clinical settings. PUBLIC HEALTH RELEVANCE: With the increasing use of bisphosphonates due to its effectiveness in multiple clinical settings, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been surfaced as a significant dental and medical problem because no definitive prevention and treatment are currently available. Although BRONJ is clinically defined as exposed bone with unhealed and opened overlaying oral mucosa, the exact role of oral mucosa in the pathophysiology of BRONJ is not fully understood. In this proposal, we will investigate direct effects of bisphosphonates on the oral mucosal cells, and our results are expected to contribute significantly on managing long-term bisphosphonate users by improving treatment and prevention modalities.
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2013 — 2017 |
Kim, Reuben Han-Kyu Wang, Cun-Yu [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Epigenetic Control of Hpv-Associated Oral Carcinogenesis @ University of California Los Angeles
DESCRIPTION (provided by applicant): The long-term objectives of this application are to understand how epigenetic mechanisms control the high-risk human papillomaviruses (HPV)-associated oral carcinogenesis. Squamous cell carcinoma (SCC) is the most common cancer arising in the oral cavity, oropharynx, head and neck. The high-risk HPV16, a small DNA virus having tropism for squamous epithelia, has been found to be associated with the development and progression of oral and oropharyngeal SCC (OSCC). More importantly, the incidence of HPV-positive OSCC has increased in the USA in the last decade. The high-risk HPV16 expresses two major oncoproteins, E6 and E7. The combination of E6 and E7 (E6/E7) potently immortalizes human oral keratinocytes and promotes oncogenesis. While significant progress has been made in understanding the molecular control of E6/E7-mediated OSCC development, little is known about the interplay between HPV infection and oral keratinocyte chromatin dynamics in OSCC development and progression. Histone methylation is an important process linked to the activation and repression of gene expression, thus playing a critical role in cell growth control and oncogenesis. To explore the epigenetic regulation of HPV-associated OSCC, we systemically profiled the expression of histone demethylases in E6/E7-expressing OSCC cells. Interestingly, we found that E6/E7 potently suppressed KDM5C (also known as SMCX) expression in OSCC cells. KDM5C is a histone demethylase which removes trimethylated histone H3 at lysine 4 (H3K4me3). H3K4me3 is an activation marker, and the inhibition of KDM5C can increase the levels of H3K4me3, leading to gene activation. As a complementary approach to gene expression profiling, our siRNA screening has identified that the histone demethylase KDM4A plays an important role in the epigenetic activation of AP-1 by removing H3K9me3. Previously, we have found that AP-1 plays a critical role in the invasive growth of OSCC which is required for the progression of carcinoma in situ to OSCC. In addition to control of E6/E7 transcription, AP-1 plays an essential role in HPV-mediated oncogenesis. Based on our exciting preliminary studies, in this new application, our novel hypothesis is that KDM5C and KDM4A epigenetically control development and progression of HPV-positive OSCC by modifying H3K4me3 and H3K9me3 marks. Three specific aims are proposed to test our hypothesis. Aim 1 is to determine whether the high-risk HPV16 E6/E7 oncoproteins epigenetically reprogram OSCCs and promote OSCC progression by inhibiting KDM5C. Aim 2 is to determine whether KDM4A epigenetically promotes E6/E7 expression through AP-1. Aim 3 is to determine whether E6/E7 activate AP-1 and promote OSCC development through KDM4A. Since histone demethylases are chemically modifiable, KDM5C and KDM4A might represent novel therapeutic targets for specifically controlling HPV-associated OSCC.
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2013 — 2017 |
Kim, Reuben Han-Kyu |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Mechanisms of Drug-Induced Onj and Osteomucosal Chronic Wounds @ University of California Los Angeles
DESCRIPTION (provided by applicant): Oral mucosa is uniquely known for its scarless and expedited wound healing compared to skin. Nonetheless, lines of evidence accumulate at the alarming rate that certain drugs used to treat bone- associated diseases specifically induce osteonecrosis of the jaw (ONJ) and delay wound healing of oral mucosa, leading to considerable clinical complications and compromising the patients' quality of life. The long- term users of these drugs, bisphosphonates (BP) and denosumab, are at the higher risk of developing ONJ, clinically defined as exposed necrotic bone with unhealed overlaying oral mucosa for at least 8 weeks. Both drugs have the common mechanisms of actions; they inhibit functions of osteoclasts, bone resorbing cells that are critically important for bone remodeling. However, the exact mechanisms as to why and how these bone- related drugs compromise the healing of the overlaying oral mucosal tissues are largely unknown. The lack of fundamental understanding in drug-induced ONJ is presumably due to the missing gaps in knowledge about osteomucosal healing, a combinatorial healing process of the soft and hard tissues as one entity that uniquely occurs in the oral cavity. To address this issue, we performed the high-throughput microarray analysis using the BRONJ mouse model at the sites of osteomucosal wounds and found series of differentially expressed genes including secretory proteins. We further developed a mouse model for DRONJ and found similar ONJ-like lesions. Based on our preliminary studies, we hypothesize that the osteomucosal wound healing is orchestrated by cross interactions among cells in soft and hard tissues via secretory proteins at the site of wound, and that drug-induced ONJ is developed by deregulating such interactions by BP and denosumab, leading to distinct molecular alterations and impaired osteomucosal healing. The objectives of this proposal are: 1) to investigate role of RANKL, a secretory protein important for bone remodeling and healing, using genetically engineered mice; 2) to identify genes/proteins that are commonly deregulated in BRONJ- and DRONJ-like lesions using the high-throughput microarray and proteomics; and 3) to investigate the cross interactions between different cell types using co-culture systems as well as our newly developed osteomucosal tissue constructs in vitro. Oral mucosal tissues are anatomically situated in close proximity to the underlying bone tissues, suggesting that the drug-induced ONJ in the oral cavity may be associated with the impaired cross-talks between these two entities during the osteomucosal wound healing processes. Current proposal would help unraveling the molecular mechanisms of rather unexplored areas of research in osteomucosal wound healing and provide knowledge for future therapeutic applications to both BRONJ and DRONJ.
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