The overarching goalsof the University of Kentucky (UK) IMERS workshops, supported by an IPERT gr... more The overarching goalsof the University of Kentucky (UK) IMERS workshops, supported by an IPERT grant, are to empower faculty at minority-serving institutions (MSIs) to develop and submit competitive research proposals through intensive grant-writing skills training;to build research-related individual and institutional capacity through training on mentorship of student researchers;and to sustain workshop momentum by embedding multiple levels of mentored proposal development support during and after each workshop. We hypothesize that this targeted training will enhance the research environment at MSI's, increase the diversity of NIH-funded investigators and improve the training of underrepresented students in biomedical research, thus providing a feed-forward mechanism to expand the diversity of the US biomedical workforce in future years. A hallmark of IMERS is to engage participants in hands-on, active-learning style grant-writing training for faculty who are poised to submit NIH proposals ranging from development/exploratory to R01s. This training is provided by UK faculty and experienced research development professionals. The IMERS model incorporates guided writing, participatory training, and active learning. Training is comprised of several modalities. First, IMERS offers two 3-day grant-writing retreats/year on the UK campus. These workshops are designed for highly motivated investigators who have submitted proposals to NIH without success and those who have been actively planning NIH submission;~25 faculty are selected for each workshop via an on-line application. On-site workshops include consultation with actively funded UK investigators and staff from the UK Proposal Development Office;we strive to maintain post-workshop interactions between participants and UK faculty/staff. Three 2-day off-site workshops/year are also offered. The IMERS staff will work with off-site institutions to tailor the workshops to specific needs. In-person workshops have been postponed due to COVID-19 restrictions, but will resume when safe to do so. However, we have developed an active series of virtual workshops and seminars during this time, and we anticipate that these and additional on-line activities will continue as a third arm of training even after restriction are lifted. Travel and lodging expenses for faculty to attend UK workshops, for the IMERS team to travel, are covered by the grant. Workshop sessions cover numerous topics, including: using NIH resources for program/funding information, budget issues, the proposal review process, writing a high-impact specific aims page and an effective research strategy, rigor and reproducibility, responsible conduct of research, NIH Biosketch, navigating the NIH resubmission process, and mentoring student researchers. Program evaluation, based in part on participant survey data, communication email and an active ListServ and subsequent submission rate and success, validates that program participants have increased confidence in their grant-writing abilities and are succeeding in obtaining NIH funding.
The mammalian cytochrome P450 (Cyp) gene family encodes a large number of structurally related en... more The mammalian cytochrome P450 (Cyp) gene family encodes a large number of structurally related enzymes that catalyze a variety of metabolic and detoxification reactions. The liver is the primary site of Cyp expression in terms of expression levels and number of expressed genes, consistent with this organ’s essential role in metabolism of endogenous and xenobiotic compounds. Many Cyp genes exhibit sexually dimorphic expression. For example, Cyp2a4 is expressed significantly higher in the adult liver of female mice compared to male mice. An exception to this pattern is seen in BALB/cJ mice, where male hepatic Cyp2a4 mRNA levels are substantially elevated compared to male mice of other strains. The Zinc fingers and homeoboxes 2 (Zhx2) protein governs the silencing of several genes in the postnatal liver, including α-fetoprotein, H19, and glypican 3. Zhx2 also regulates numerous hepatic genes that govern lipid homeostasis. We previously showed that the Zhx2 gene is mutated in BALB/cJ mi...
BALB/cJ mice exhibit considerable phenotypic differences with other BALB/c substrains. Some of th... more BALB/cJ mice exhibit considerable phenotypic differences with other BALB/c substrains. Some of these traits involve the liver, including persistent postnatal expression of genes that are normally expressed only in the fetal liver and reduced expression of major urinary proteins. These traits are due to a mutation that dramatically reduces expression of the gene encoding the transcription factor Zinc fingers and homeoboxes 2 (Zhx2). BALB/cJ mice also exhibit reduced serum lipid levels and resistance to atherosclerosis compared to other mouse strains when placed on a high-fat diet. This trait is also due, at least in part, to the Zhx2 mutation. Microarray analysis identified many genes affecting lipid homeostasis, including Lipoprotein lipase, that are dysregulated in BALB/cJ liver. This led us to investigate whether hepatic lipid levels would be different between BALB/cJ and BALB/c mice when placed on a normal chow or a high-fat chow diet. On the high-fat chow, BALB/cJ mice had increased weight gain, increased liver:body weight ratio, elevated hepatic lipid accumulation and markers of liver damage when compared to BALB/c mice. These traits in BALB/cJ mice were only partially reversed by a hepatocyte-specific Zhx2 transgene. These data indicate that Zhx2 reduces liver lipid levels and is hepatoprotective in mice on a high-fat diet, but the partial rescue by the Zhx2 transgene suggests a contribution by both parenchymal and non-parenchymal cells. A model to account for the cardiovascular and liver phenotype in mice with reduced Zhx2 levels is provided.
Initiation of hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection is a co... more Initiation of hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection is a complex process that includes both oncogene activation and tumor suppressor inhibition. The HBV X (HBx) protein has an important and complex role in processes leading to HCC. We previously identified the mammalian Zinc fingers and homeoboxes 2 (ZHX2) gene as an HCC-associated tumor suppressor gene. In the present study, we investigated whether the oncogenic properties of HBV and, more specifically, HBx, involved ZHX2 silencing. Our data indicates that ZHX2 expression is significantly decreased in tumor tissues from HBV-positive HCC patients and livers from HBV transgenic mice. In vitro and in vivo studies confirmed that HBV-encoded proteins, particularly HBx, inhibits both the expression and tumor suppression properties of ZHX2. Further analyses identified miR-155, a well-known oncomiR in various cancers, as an important link between HBx and ZHX2 inhibition. Increased miR-155 levels were f...
ABSTRACT In this review, the role of NF-κB in the induction of hepatocarcinogenesis by peroxis... more ABSTRACT In this review, the role of NF-κB in the induction of hepatocarcinogenesis by peroxisome proliferators is examined. The administration of peroxisome proliferators for more than a three-day period leads to the activation of NF-κB in the livers of rats and mice. On the other hand, peroxisome proliferator activated receptor-α (PPARα) activation in non-hepatic tissues can lead to the inhibition of NF-κB activation. Several lines of evidence support the hypothesis that the activation of NF-κB by peroxisome proliferators in the liver is mediated by oxidative stress. The role of NF-κB in peroxisome proliferator-induced hepatocarcinogenesis has been examined using NF-κB knockout models. Specifically, the induction of cell proliferation and the promotion of liver carcinogenesis are inhibited in mice lacking the p50 subunit of NF-κB. Overall, the activation of NF-κB appears to be important in the carcinogenic activity of peroxisome proliferators.
The overarching goalsof the University of Kentucky (UK) IMERS workshops, supported by an IPERT gr... more The overarching goalsof the University of Kentucky (UK) IMERS workshops, supported by an IPERT grant, are to empower faculty at minority-serving institutions (MSIs) to develop and submit competitive research proposals through intensive grant-writing skills training;to build research-related individual and institutional capacity through training on mentorship of student researchers;and to sustain workshop momentum by embedding multiple levels of mentored proposal development support during and after each workshop. We hypothesize that this targeted training will enhance the research environment at MSI's, increase the diversity of NIH-funded investigators and improve the training of underrepresented students in biomedical research, thus providing a feed-forward mechanism to expand the diversity of the US biomedical workforce in future years. A hallmark of IMERS is to engage participants in hands-on, active-learning style grant-writing training for faculty who are poised to submit NIH proposals ranging from development/exploratory to R01s. This training is provided by UK faculty and experienced research development professionals. The IMERS model incorporates guided writing, participatory training, and active learning. Training is comprised of several modalities. First, IMERS offers two 3-day grant-writing retreats/year on the UK campus. These workshops are designed for highly motivated investigators who have submitted proposals to NIH without success and those who have been actively planning NIH submission;~25 faculty are selected for each workshop via an on-line application. On-site workshops include consultation with actively funded UK investigators and staff from the UK Proposal Development Office;we strive to maintain post-workshop interactions between participants and UK faculty/staff. Three 2-day off-site workshops/year are also offered. The IMERS staff will work with off-site institutions to tailor the workshops to specific needs. In-person workshops have been postponed due to COVID-19 restrictions, but will resume when safe to do so. However, we have developed an active series of virtual workshops and seminars during this time, and we anticipate that these and additional on-line activities will continue as a third arm of training even after restriction are lifted. Travel and lodging expenses for faculty to attend UK workshops, for the IMERS team to travel, are covered by the grant. Workshop sessions cover numerous topics, including: using NIH resources for program/funding information, budget issues, the proposal review process, writing a high-impact specific aims page and an effective research strategy, rigor and reproducibility, responsible conduct of research, NIH Biosketch, navigating the NIH resubmission process, and mentoring student researchers. Program evaluation, based in part on participant survey data, communication email and an active ListServ and subsequent submission rate and success, validates that program participants have increased confidence in their grant-writing abilities and are succeeding in obtaining NIH funding.
The mammalian cytochrome P450 (Cyp) gene family encodes a large number of structurally related en... more The mammalian cytochrome P450 (Cyp) gene family encodes a large number of structurally related enzymes that catalyze a variety of metabolic and detoxification reactions. The liver is the primary site of Cyp expression in terms of expression levels and number of expressed genes, consistent with this organ’s essential role in metabolism of endogenous and xenobiotic compounds. Many Cyp genes exhibit sexually dimorphic expression. For example, Cyp2a4 is expressed significantly higher in the adult liver of female mice compared to male mice. An exception to this pattern is seen in BALB/cJ mice, where male hepatic Cyp2a4 mRNA levels are substantially elevated compared to male mice of other strains. The Zinc fingers and homeoboxes 2 (Zhx2) protein governs the silencing of several genes in the postnatal liver, including α-fetoprotein, H19, and glypican 3. Zhx2 also regulates numerous hepatic genes that govern lipid homeostasis. We previously showed that the Zhx2 gene is mutated in BALB/cJ mi...
BALB/cJ mice exhibit considerable phenotypic differences with other BALB/c substrains. Some of th... more BALB/cJ mice exhibit considerable phenotypic differences with other BALB/c substrains. Some of these traits involve the liver, including persistent postnatal expression of genes that are normally expressed only in the fetal liver and reduced expression of major urinary proteins. These traits are due to a mutation that dramatically reduces expression of the gene encoding the transcription factor Zinc fingers and homeoboxes 2 (Zhx2). BALB/cJ mice also exhibit reduced serum lipid levels and resistance to atherosclerosis compared to other mouse strains when placed on a high-fat diet. This trait is also due, at least in part, to the Zhx2 mutation. Microarray analysis identified many genes affecting lipid homeostasis, including Lipoprotein lipase, that are dysregulated in BALB/cJ liver. This led us to investigate whether hepatic lipid levels would be different between BALB/cJ and BALB/c mice when placed on a normal chow or a high-fat chow diet. On the high-fat chow, BALB/cJ mice had increased weight gain, increased liver:body weight ratio, elevated hepatic lipid accumulation and markers of liver damage when compared to BALB/c mice. These traits in BALB/cJ mice were only partially reversed by a hepatocyte-specific Zhx2 transgene. These data indicate that Zhx2 reduces liver lipid levels and is hepatoprotective in mice on a high-fat diet, but the partial rescue by the Zhx2 transgene suggests a contribution by both parenchymal and non-parenchymal cells. A model to account for the cardiovascular and liver phenotype in mice with reduced Zhx2 levels is provided.
Initiation of hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection is a co... more Initiation of hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection is a complex process that includes both oncogene activation and tumor suppressor inhibition. The HBV X (HBx) protein has an important and complex role in processes leading to HCC. We previously identified the mammalian Zinc fingers and homeoboxes 2 (ZHX2) gene as an HCC-associated tumor suppressor gene. In the present study, we investigated whether the oncogenic properties of HBV and, more specifically, HBx, involved ZHX2 silencing. Our data indicates that ZHX2 expression is significantly decreased in tumor tissues from HBV-positive HCC patients and livers from HBV transgenic mice. In vitro and in vivo studies confirmed that HBV-encoded proteins, particularly HBx, inhibits both the expression and tumor suppression properties of ZHX2. Further analyses identified miR-155, a well-known oncomiR in various cancers, as an important link between HBx and ZHX2 inhibition. Increased miR-155 levels were f...
ABSTRACT In this review, the role of NF-κB in the induction of hepatocarcinogenesis by peroxis... more ABSTRACT In this review, the role of NF-κB in the induction of hepatocarcinogenesis by peroxisome proliferators is examined. The administration of peroxisome proliferators for more than a three-day period leads to the activation of NF-κB in the livers of rats and mice. On the other hand, peroxisome proliferator activated receptor-α (PPARα) activation in non-hepatic tissues can lead to the inhibition of NF-κB activation. Several lines of evidence support the hypothesis that the activation of NF-κB by peroxisome proliferators in the liver is mediated by oxidative stress. The role of NF-κB in peroxisome proliferator-induced hepatocarcinogenesis has been examined using NF-κB knockout models. Specifically, the induction of cell proliferation and the promotion of liver carcinogenesis are inhibited in mice lacking the p50 subunit of NF-κB. Overall, the activation of NF-κB appears to be important in the carcinogenic activity of peroxisome proliferators.
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