This is an application for the Independent Scientist Award (K02) from Mo Kwan Kang, DOS, PhD, Assistant Professor at the UCLA School of Dentistry. The long-term goal of Dr. Kang's research program is to promote oral mucosal health in the patients affected by human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS).
He aims to achieve these goals by developing novel approaches to prevent the oral mucosal complications of antiretroviral therapies (ART). Dr. Kang has recently been awarded a new R01 grant to elucidate the effects of ART on telomerase function in human oral epithelium. This is a new area of investigation for Dr. Kang, whose past research has focused on oral epithelial biology using normal human oral keratinocytes (NHOK) as a model system. The purpose of the current K02 application is to extend Dr. Kang's current research by (1) gaining new knowledge in the basic and clinical sciences of HIV and AIDS, (2) establishing the 3-dimensional cell culture model system of oral epithelium to enhance his ongoing and future research, and (3) developing an animal model with which to study the effects of RTIs on human oral epithelium in vivo. The research plan will test the central hypothesis: Telomerase inhibition in NHOK by RTIs is responsible for the diminution of regenerative capacity of the oral epithelium and adverse oral mucosal complications associated with long-term administration of ART in HIV+ patients. To test this hypothesis, Dr. Kang proposed three Specific Aims: (1) to determine the telomerase activity, telomeric status, and cellular phenotypic alteration in NHOK exposed to RTIs;(2) to determine the effects of RTI on the DNA repair activities, mutation frequency, and genetic integrity in NHOK;and (3) to investigate the effects of azidothymidine (AZT) on phenotypic alterations in NHOK expressing exogenous telomerase or acquiring enhanced replication potential.
The Aims 1 and 2 will investigate detailed phenotypic and genetic effects of RTIs in oral epithelium.
Aim 3 will determine whether augmenting cellular telomerase activity and/or "priming" the cells with enhanced replicative potential can prevent the adverse phenotypic effects of AZT. The outcome of this project will be used to develop novel adjunctive therapies to prevent the oral mucosal complications of long-term administration of antiretroviral medications in HIV+ patients. This will fulfill the ultimate objectives of Dr. Kang's research to enhance the oral mucosal health of the patients affected by HIV and AIDS.
|Dong, Qinghua; Oh, Ju-Eun; Yi, Jin Kyu et al. (2013) Efavirenz induces autophagy and aberrant differentiation in normal human keratinocytes. Int J Mol Med 31:1305-12|
|Kim, Reuben H; Williams, Drake W; Bae, Susan et al. (2013) Camphorquinone inhibits odontogenic differentiation of dental pulp cells and triggers release of inflammatory cytokines. J Endod 39:57-61|
|Mehrazarin, Shebli; Oh, Ju Eun; Chung, Christine L et al. (2011) Impaired odontogenic differentiation of senescent dental mesenchymal stem cells is associated with loss of Bmi-1 expression. J Endod 37:662-6|
|Dong, Qinghua; Oh, Ju-Eun; Chen, Wei et al. (2011) Radioprotective effects of Bmi-1 involve epigenetic silencing of oxidase genes and enhanced DNA repair in normal human keratinocytes. J Invest Dermatol 131:1216-25|
|Oh, Ju-Eun; Kim, Reuben H; Shin, Ki-Hyuk et al. (2011) DeltaNp63ýý protein triggers epithelial-mesenchymal transition and confers stem cell properties in normal human keratinocytes. J Biol Chem 286:38757-67|
|Kim, R H; Lee, R S; Williams, D et al. (2011) Bisphosphonates induce senescence in normal human oral keratinocytes. J Dent Res 90:810-6|
|Shin, Ki-Hyuk; Pucar, Ana; Kim, Reuben H et al. (2011) Identification of senescence-inducing microRNAs in normal human keratinocytes. Int J Oncol 39:1205-11|
|Chen, Wei; Dong, Qinghua; Shin, Ki-Hyuk et al. (2010) Grainyhead-like 2 enhances the human telomerase reverse transcriptase gene expression by inhibiting DNA methylation at the 5'-CpG island in normal human keratinocytes. J Biol Chem 285:40852-63|
|Kim, Reuben H; Lieberman, Mark B; Lee, Rachel et al. (2010) Bmi-1 extends the life span of normal human oral keratinocytes by inhibiting the TGF-beta signaling. Exp Cell Res 316:2600-8|
|Kang, X; Chen, W; Kim, R H et al. (2009) Regulation of the hTERT promoter activity by MSH2, the hnRNPs K and D, and GRHL2 in human oral squamous cell carcinoma cells. Oncogene 28:565-74|
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