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Holly Morrison is a PhD candidate at the Virginia-Maryland College of Veterinary Medicine. She studies the noncanonical NF-κB signaling pathway and how dysregulation of this pathway has implications on gastrointestinal diseases, including colorectal cancer, eosinophilic esophagitis, and inflammatory bowel disease. Her research areas of focus include immunology, genetics, and microbiology. She continues to conduct translational studies with the hopes of benefitting both the veterinary and human medical fields.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a ‘cytokine storm.’ In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation.
Victoria Callahan; Seth Hawks; Matthew Crawford; Caitlin Lehman; Holly Morrison; Hannah Ivester; Ivan Akhrymuk; Niloufar Boghdeh; Rafaela Flor; Carla Finkielstein; Irving Allen; James Weger-Lucarelli; Nisha Duggal; Molly Hughes; Kylene Kehn-Hall. The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner. Viruses 2021, 13, 1062 .
AMA StyleVictoria Callahan, Seth Hawks, Matthew Crawford, Caitlin Lehman, Holly Morrison, Hannah Ivester, Ivan Akhrymuk, Niloufar Boghdeh, Rafaela Flor, Carla Finkielstein, Irving Allen, James Weger-Lucarelli, Nisha Duggal, Molly Hughes, Kylene Kehn-Hall. The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner. Viruses. 2021; 13 (6):1062.
Chicago/Turabian StyleVictoria Callahan; Seth Hawks; Matthew Crawford; Caitlin Lehman; Holly Morrison; Hannah Ivester; Ivan Akhrymuk; Niloufar Boghdeh; Rafaela Flor; Carla Finkielstein; Irving Allen; James Weger-Lucarelli; Nisha Duggal; Molly Hughes; Kylene Kehn-Hall. 2021. "The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner." Viruses 13, no. 6: 1062.
New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients’ anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.
Alissa Hendricks-Wenger; Kenneth N. Aycock; Margaret A. Nagai-Singer; Sheryl Coutermarsh-Ott; Melvin F. Lorenzo; Jessica Gannon; Kyungjun Uh; Kayla Farrell; Natalie Beitel-White; Rebecca M. Brock; Alexander Simon; Holly A. Morrison; Joanne Tuohy; Sherrie Clark-Deener; Eli Vlaisavljevich; Rafael V. Davalos; Kiho Lee; Irving C. Allen. Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation. Scientific Reports 2021, 11, 1 -14.
AMA StyleAlissa Hendricks-Wenger, Kenneth N. Aycock, Margaret A. Nagai-Singer, Sheryl Coutermarsh-Ott, Melvin F. Lorenzo, Jessica Gannon, Kyungjun Uh, Kayla Farrell, Natalie Beitel-White, Rebecca M. Brock, Alexander Simon, Holly A. Morrison, Joanne Tuohy, Sherrie Clark-Deener, Eli Vlaisavljevich, Rafael V. Davalos, Kiho Lee, Irving C. Allen. Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation. Scientific Reports. 2021; 11 (1):1-14.
Chicago/Turabian StyleAlissa Hendricks-Wenger; Kenneth N. Aycock; Margaret A. Nagai-Singer; Sheryl Coutermarsh-Ott; Melvin F. Lorenzo; Jessica Gannon; Kyungjun Uh; Kayla Farrell; Natalie Beitel-White; Rebecca M. Brock; Alexander Simon; Holly A. Morrison; Joanne Tuohy; Sherrie Clark-Deener; Eli Vlaisavljevich; Rafael V. Davalos; Kiho Lee; Irving C. Allen. 2021. "Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation." Scientific Reports 11, no. 1: 1-14.
Persulfides (R−SSH) have been hypothesized as potent redox modulators and signaling compounds. Reported herein is the synthesis, characterization, and in vivo evaluation of a persulfide donor that releases N‐acetyl cysteine persulfide (NAC‐SSH) in response to the prokaryote‐specific enzyme nitroreductase. The donor, termed NDP‐NAC, decomposed in response to E. coli nitroreductase, resulting in release of NAC‐SSH. NDP‐NAC elicited gastroprotective effects in mice that were not observed in animals treated with control compounds incapable of persulfide release or in animals treated with Na2S. NDP‐NAC induced these effects by the upregulation of beneficial small‐ and medium‐chain fatty acids and through increasing growth of Turicibacter sanguinis, a beneficial gut bacterium. It also decreased the populations of Synergistales bacteria, opportunistic pathogens implicated in gastrointestinal infections. This study reveals the possibility of maintaining gut health or treating microbiome‐related diseases by the targeted delivery of reactive sulfur species.
Kearsley M. Dillon; Holly A. Morrison; Chadwick R. Powell; Ryan J. Carrazzone; Veronica M. Ringel‐Scaia; Ethan W. Winckler; R. McAlister Council‐Troche; Irving C. Allen; John B. Matson. Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome. Angewandte Chemie 2021, 133, 6126 -6132.
AMA StyleKearsley M. Dillon, Holly A. Morrison, Chadwick R. Powell, Ryan J. Carrazzone, Veronica M. Ringel‐Scaia, Ethan W. Winckler, R. McAlister Council‐Troche, Irving C. Allen, John B. Matson. Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome. Angewandte Chemie. 2021; 133 (11):6126-6132.
Chicago/Turabian StyleKearsley M. Dillon; Holly A. Morrison; Chadwick R. Powell; Ryan J. Carrazzone; Veronica M. Ringel‐Scaia; Ethan W. Winckler; R. McAlister Council‐Troche; Irving C. Allen; John B. Matson. 2021. "Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome." Angewandte Chemie 133, no. 11: 6126-6132.
Persulfides (R−SSH) have been hypothesized as potent redox modulators and signaling compounds. Reported herein is the synthesis, characterization, and in vivo evaluation of a persulfide donor that releases N‐acetyl cysteine persulfide (NAC‐SSH) in response to the prokaryote‐specific enzyme nitroreductase. The donor, termed NDP‐NAC, decomposed in response to E. coli nitroreductase, resulting in release of NAC‐SSH. NDP‐NAC elicited gastroprotective effects in mice that were not observed in animals treated with control compounds incapable of persulfide release or in animals treated with Na2S. NDP‐NAC induced these effects by the upregulation of beneficial small‐ and medium‐chain fatty acids and through increasing growth of Turicibacter sanguinis, a beneficial gut bacterium. It also decreased the populations of Synergistales bacteria, opportunistic pathogens implicated in gastrointestinal infections. This study reveals the possibility of maintaining gut health or treating microbiome‐related diseases by the targeted delivery of reactive sulfur species.
Kearsley M. Dillon; Holly A. Morrison; Chadwick R. Powell; Ryan J. Carrazzone; Veronica M. Ringel‐Scaia; Ethan W. Winckler; R. McAlister Council‐Troche; Irving C. Allen; John B. Matson. Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome. Angewandte Chemie International Edition 2021, 60, 6061 -6067.
AMA StyleKearsley M. Dillon, Holly A. Morrison, Chadwick R. Powell, Ryan J. Carrazzone, Veronica M. Ringel‐Scaia, Ethan W. Winckler, R. McAlister Council‐Troche, Irving C. Allen, John B. Matson. Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome. Angewandte Chemie International Edition. 2021; 60 (11):6061-6067.
Chicago/Turabian StyleKearsley M. Dillon; Holly A. Morrison; Chadwick R. Powell; Ryan J. Carrazzone; Veronica M. Ringel‐Scaia; Ethan W. Winckler; R. McAlister Council‐Troche; Irving C. Allen; John B. Matson. 2021. "Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome." Angewandte Chemie International Edition 60, no. 11: 6061-6067.
Breast cancer is a devastating malignancy, accounting for 40,000 female deaths and 30% of new female cancer diagnoses in the United States in 2019 alone. The leading cause of breast cancer related deaths is the metastatic burden. Therefore, preclinical models for breast cancer need to analyze metastatic burden to be clinically relevant. The 4T1 breast cancer model provides a spontaneously-metastasizing, quantifiable mouse model for stage IV human breast cancer. However, most 4T1 protocols quantify the metastatic burden by manually counting stained colonies on tissue culture plates. While this is sufficient for tissues with lower metastatic burden, human error in manual counting causes inconsistent and variable results when plates are confluent and difficult to count. This method offers a computer-based solution to human counting error. Here, we evaluate the protocol using the lung, a highly metastatic tissue in the 4T1 model. Images of methylene blue-stained plates are acquired and uploaded for analysis in Fiji-ImageJ. Fiji-ImageJ then determines the percentage of the selected area of the image that is blue, representing the percentage of the plate with metastatic burden. This computer-based approach offers more consistent and expeditious results than manual counting or histopathological evaluation for highly metastatic tissues. The consistency of Fiji-ImageJ results depends on the quality of the image. Slight variations in results between images can occur, thus it is recommended that multiple images are taken and results averaged. Despite its minimal limitations, this method is an improvement to quantifying metastatic burden in the lung by offering consistent and rapid results.
Margaret A. Nagai-Singer; Alissa Hendricks-Wenger; Rebecca M. Brock; Holly A. Morrison; Juselyn D. Tupik; Sheryl Coutermarsh-Ott; Irving C. Allen. Using Computer-based Image Analysis to Improve Quantification of Lung Metastasis in the 4T1 Breast Cancer Model. Journal of Visualized Experiments 2020, e61805 .
AMA StyleMargaret A. Nagai-Singer, Alissa Hendricks-Wenger, Rebecca M. Brock, Holly A. Morrison, Juselyn D. Tupik, Sheryl Coutermarsh-Ott, Irving C. Allen. Using Computer-based Image Analysis to Improve Quantification of Lung Metastasis in the 4T1 Breast Cancer Model. Journal of Visualized Experiments. 2020; (164):e61805.
Chicago/Turabian StyleMargaret A. Nagai-Singer; Alissa Hendricks-Wenger; Rebecca M. Brock; Holly A. Morrison; Juselyn D. Tupik; Sheryl Coutermarsh-Ott; Irving C. Allen. 2020. "Using Computer-based Image Analysis to Improve Quantification of Lung Metastasis in the 4T1 Breast Cancer Model." Journal of Visualized Experiments , no. 164: e61805.
Coal is one of the most abundant and economic sources for global energy production. However, the burning of coal is widely recognized as a significant contributor to atmospheric particulate matter linked to deleterious respiratory impacts. Recently, we have discovered that burning coal generates large quantities of otherwise rare Magnéli phase titanium suboxides from TiO2 minerals naturally present in coal. These nanoscale Magnéli phases are biologically active without photostimulation and toxic to airway epithelial cells in vitro and to zebrafish in vivo. Here, we sought to determine the clinical and physiological impact of pulmonary exposure to Magnéli phases using mice as mammalian model organisms. Mice were exposed to the most frequently found Magnéli phases, Ti6O11, at 100 parts per million (ppm) via intratracheal administration. Local and systemic titanium concentrations, lung pathology, and changes in airway mechanics were assessed. Additional mechanistic studies were conducted with primary bone marrow derived macrophages. Our results indicate that macrophages are the cell type most impacted by exposure to these nanoscale particles. Following phagocytosis, macrophages fail to properly eliminate Magnéli phases, resulting in increased oxidative stress, mitochondrial dysfunction, and ultimately apoptosis. In the lungs, these nanoparticles become concentrated in macrophages, resulting in a feedback loop of reactive oxygen species production, cell death, and the initiation of gene expression profiles consistent with lung injury within 6 weeks of exposure. Chronic exposure and accumulation of Magnéli phases ultimately results in significantly reduced lung function impacting airway resistance, compliance, and elastance. Together, these studies demonstrate that Magnéli phases are toxic in the mammalian airway and are likely a significant nanoscale environmental pollutant, especially in geographic regions where coal combustion is a major contributor to atmospheric particulate matter.
Dylan K. McDaniel; Veronica M. Ringel-Scaia; Holly A. Morrison; Sheryl Coutermarsh-Ott; McAlister Council-Troche; Jonathan W. Angle; Justin B. Perry; Grace Davis; Weinan Leng; Valerie Minarchick; Yi Yang; Bo Chen; Sky W. Reece; David A. Brown; Thomas E. Cecere; Jared M. Brown; Kymberly M. Gowdy; Michael F. Jr. Hochella; Irving C. Allen. Pulmonary Exposure to Magnéli Phase Titanium Suboxides Results in Significant Macrophage Abnormalities and Decreased Lung Function. Frontiers in Immunology 2019, 10, 2714 .
AMA StyleDylan K. McDaniel, Veronica M. Ringel-Scaia, Holly A. Morrison, Sheryl Coutermarsh-Ott, McAlister Council-Troche, Jonathan W. Angle, Justin B. Perry, Grace Davis, Weinan Leng, Valerie Minarchick, Yi Yang, Bo Chen, Sky W. Reece, David A. Brown, Thomas E. Cecere, Jared M. Brown, Kymberly M. Gowdy, Michael F. Jr. Hochella, Irving C. Allen. Pulmonary Exposure to Magnéli Phase Titanium Suboxides Results in Significant Macrophage Abnormalities and Decreased Lung Function. Frontiers in Immunology. 2019; 10 ():2714.
Chicago/Turabian StyleDylan K. McDaniel; Veronica M. Ringel-Scaia; Holly A. Morrison; Sheryl Coutermarsh-Ott; McAlister Council-Troche; Jonathan W. Angle; Justin B. Perry; Grace Davis; Weinan Leng; Valerie Minarchick; Yi Yang; Bo Chen; Sky W. Reece; David A. Brown; Thomas E. Cecere; Jared M. Brown; Kymberly M. Gowdy; Michael F. Jr. Hochella; Irving C. Allen. 2019. "Pulmonary Exposure to Magnéli Phase Titanium Suboxides Results in Significant Macrophage Abnormalities and Decreased Lung Function." Frontiers in Immunology 10, no. : 2714.
Over the last decade, significant progress has been achieved in defining mechanisms underlying NLR regulation of immune system function. However, several NLR family members continue to defy our best attempts at characterization and routinely exhibit confounding data. This is particularly true for NLR family members that regulate signaling associated with the activation of other pattern recognition receptors. NLRX1 is a member of this NLR sub-group and acts as an enigmatic regulator of immune system function. NLRX1 has been shown to negatively regulate type-I interferon, attenuate pro-inflammatory NF-κB signaling, promote reactive oxygen species production, and modulate autophagy, cell death, and proliferation. However, the mechanism/s associated with NLRX1 modulation of these pathways is not fully understood and there are inconsistencies within the field. Likewise, it is highly likely that the full repertoire of biological functions impacted by NLRX1 are yet to be defined. Recent mouse studies have shown that NLRX1 significantly impacts a multitude of diseases, including cancer, virus infection, osteoarthritis, traumatic brain injury, and inflammatory bowel disease. Thus, it is essential that the underlying mechanism associated with NLRX1 function in each of these diseases be robustly defined. Here, we summarize the current progress in understanding mechanisms associated with NLRX1 function. We also offer insight into both unique and overlapping mechanisms regulated by NLRX1 that likely contribute to disease pathobiology. Ultimately, we believe that an improved understanding of NLRX1 will result in better defined mechanisms associated with immune system attenuation and the resolution of inflammation in a myriad of diseases.
Margaret A. Nagai-Singer; Holly A. Morrison; Irving C. Allen. NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function. Frontiers in Immunology 2019, 10, 2419 .
AMA StyleMargaret A. Nagai-Singer, Holly A. Morrison, Irving C. Allen. NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function. Frontiers in Immunology. 2019; 10 ():2419.
Chicago/Turabian StyleMargaret A. Nagai-Singer; Holly A. Morrison; Irving C. Allen. 2019. "NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function." Frontiers in Immunology 10, no. : 2419.