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THE ROLE OF ACTIVIN A SIGNALING IN GASTRIC REFLUX-RELATED DISEASES AND THE PROGRESSION TO ESOPHAGEAL ADENOCARCINOMA
Title
THE ROLE OF ACTIVIN A SIGNALING IN GASTRIC REFLUX-RELATED DISEASES AND THE PROGRESSION TO ESOPHAGEAL ADENOCARCINOMA.
Creator
Roudebush, Cedric J., Andl, Claudia, University of Central Florida
Abstract / Description
Gastroesophageal reflux disease (GERD), or acid reflux, affects 6-9 million people in the United States. It is characterized by a reflux of gastric acid and bile salts from the stomach into the esophagus, causing injuries to the esophagus known as Barrett's esophagus (BE). BE is the main risk factor for the development of esophageal adenocarcinoma (EAC), a devastating cancer in the esophagus whose molecular roots remain poorly understood. In recent years, evidence points to the esophageal...
Show moreGastroesophageal reflux disease (GERD), or acid reflux, affects 6-9 million people in the United States. It is characterized by a reflux of gastric acid and bile salts from the stomach into the esophagus, causing injuries to the esophagus known as Barrett's esophagus (BE). BE is the main risk factor for the development of esophageal adenocarcinoma (EAC), a devastating cancer in the esophagus whose molecular roots remain poorly understood. In recent years, evidence points to the esophageal epithelium itself as responsible for causing and promoting inflammation upon injury by gastric reflux, namely via an increase in inflammatory cytokine secretion. This project was focused on a cytokine of interest, Activin A, which is known for its importance during embryogenesis and stem cell differentiation. It has recently been studied for its role in inflammation and tumor formation, but not in the case of esophageal diseases. Here, we demonstrate that Activin A signaling in esophageal epithelial cells is heavily upregulated shortly after exposure to bile salts and acid. We show evidence that this upregulation causes an increase in cell migration upon a reconstituted extracellular matrix. We also provide further evidence that bile and acid injury causes epithelial cells to secrete cytokines, which drive inflammation. We show that the upregulated Activin A secretion and signaling plays an important role in promoting this inflammatory state. Finally, we provide evidence that bile salts and acid exposure, as well as increased Activin A signaling, causes esophageal epithelial cells to upregulate stem cell and transdifferentiation markers, supporting the latest theories on the origin of Barrett' esophagus stem cells as well as paligenosis.
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Date Issued
2019
Identifier
CFH2000485, ucf:45887
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000485
USING LOW-COHERENCE INTERFEROMETRY TO MONITOR CELL INVASION IN AN IN-VITRO MODEL SYSTEM
Title
USING LOW-COHERENCE INTERFEROMETRY TO MONITOR CELL INVASION IN AN IN-VITRO MODEL SYSTEM.
Creator
Davoudi Nasab, Behnaz, Dogariu, Aristide, Andl, Claudia, University of Central Florida
Abstract / Description
In an optically random system, such as naturally occurring and man-made media, light undergoes pronounced multiple scattering. This phenomenon has shown a remarkable potential in characterizing complex materials. In this regime, scattering occurs from each individual center of the scattering and independent scattering events lead to multiple light scattering. This phenomenon is often described as a random walk of photons and can be modeled in terms of a diffusion equation based on the...
Show moreIn an optically random system, such as naturally occurring and man-made media, light undergoes pronounced multiple scattering. This phenomenon has shown a remarkable potential in characterizing complex materials. In this regime, scattering occurs from each individual center of the scattering and independent scattering events lead to multiple light scattering. This phenomenon is often described as a random walk of photons and can be modeled in terms of a diffusion equation based on the radiative transfer theory. In this thesis, we used optical path-length spectroscopy (OPS), which is an experimental method to obtain the path-length probability density of the propagating light in multiple scattering media, with a low-coherence optical field to investigate the distribution of photon path lengths in a skin cell model system. This method is capable of measuring the transport mean free path of light in a highly scattering medium and depth-resolved profiles of the backscattered light. Our OPS experimental configuration is based on a fiber-optic Michelson interferometer geometry using single mode optical fibers. We performed OPS based on low-coherence interferometry (LCI) on three-dimensional organotypic models of esophageal cell invasion by measuring the optical path-length distribution of backscattered light in normal and invasive conditions. The optical path-length distribution of light waves inside the cell samples provides information on how a change in the extracellular matrix affects invasiveness of the esophageal cells and induction of signaling pathways. Also, we demonstrated the compatibility to study the structural changes during a two-week period for in vitro cell samples.
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Date Issued
2017
Identifier
CFH2000219, ucf:45955
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000219
Malondialdehyde (MDA) and Glutathione Peroxidase (GPx) are elevated in Crohns disease-associated with Mycobacterium avium subspecies paratuberculosis (MAP)
Title
Malondialdehyde (MDA) and Glutathione Peroxidase (GPx) are elevated in Crohns disease-associated with Mycobacterium avium subspecies paratuberculosis (MAP).
Creator
Qasem, Ahmad, Naser, Saleh, Masternak, Michal, Parthasarathy, Sampath, Andl, Claudia, University of Central Florida
Abstract / Description
Inflamed tissue in Crohn's disease (CD) are continuously producing toxic oxygen metabolites leading to cellular injury and apoptosis. Here, we are evaluating the role of Mycobacterium avium subspecies paratuberculosis (MAP) in oxidative stress in CD by evaluation of lipid peroxidation and antioxidant defense activity. Specifically, we measured malondialdehyde (MDA) level and selenium-dependent glutathione peroxidase (GPx) activity in the plasma from patients and cattle infected with MAP. The...
Show moreInflamed tissue in Crohn's disease (CD) are continuously producing toxic oxygen metabolites leading to cellular injury and apoptosis. Here, we are evaluating the role of Mycobacterium avium subspecies paratuberculosis (MAP) in oxidative stress in CD by evaluation of lipid peroxidation and antioxidant defense activity. Specifically, we measured malondialdehyde (MDA) level and selenium-dependent glutathione peroxidase (GPx) activity in the plasma from patients and cattle infected with MAP. The level of MAP antibodies in bovine sera was determined by IDEXX kit whereas detection of MAP DNA was performed by IS900-based nPCR. A total of 42 cattle (21 infected with MAP and 21 healthy controls), 27 CD subjects, 27 of CD-healthy relatives, 66 subjects with various diseases and 34 non-related healthy subjects were investigated. Overall, GPx activity was significantly higher in MAP infected humans (0.80941(&)#177;0.521) versus MAP (-ve) samples (0.42367(&)#177;0.229 units/ml), P(<)0.01. Similarly, the average of GPx activity in cattle infected with MAP was 1.59(&)#177;0.65 units/ml compared to 0.46907(&)#177;0.28 units/ml in healthy cattle (P(<)0.01). Although it was not statistically significant, MDA average level was higher in MAP infected human samples versus MAP (-ve) controls (1.11(&)#177;0.185 nmol/ml versus 0.805(&)#177;0.151 nmol/ml, respectively). Similarly, MDA average level in CD samples that are MAP+ (1.703(&)#177;0.231 nmol/ml) was higher than CD samples that are MAP (-ve) (1.429(&)#177;0.187 nmol/ml). In cattle, MDA average level in MAP infected samples was significantly higher at 3.818(&)#177;0.45 nmol/ml compared to 0.538(&)#177;0.18 nmol/ml in healthy cattle (P(<)0.01). Clearly, the data demonstrated that MAP infection is associated with oxidative stress and resulting in the pathophysiology of worsening of the condition of CD patients.
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Date Issued
2016
Identifier
CFE0006699, ucf:51906
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0006699
Investigating changes in quiescence in oral and esophageal epithelium in response to injury
Title
Investigating changes in quiescence in oral and esophageal epithelium in response to injury.
Creator
Rothaus, Alexandra, Andl, Claudia, Chakrabarti, Ratna, Singla, Dinender, University of Central Florida
Abstract / Description
More than 570,000 new cases of esophageal cancer are estimated to be diagnosed annually worldwide. Risk factors include gender, age, tobacco use and dietary habits leading to tissue injury and ultimately cancer. While prognoses for other cancers have improved, the 5-year survival for patients with esophageal cancer is only 20%. During the repair process, cell proliferation is increased and is associated with inflammation. Slow-cycling lifetime residential stem cells, called quiescent cells,...
Show moreMore than 570,000 new cases of esophageal cancer are estimated to be diagnosed annually worldwide. Risk factors include gender, age, tobacco use and dietary habits leading to tissue injury and ultimately cancer. While prognoses for other cancers have improved, the 5-year survival for patients with esophageal cancer is only 20%. During the repair process, cell proliferation is increased and is associated with inflammation. Slow-cycling lifetime residential stem cells, called quiescent cells, facilitate repair but are thought to accumulate mutations during DNA replication eventually giving rise to cancer. We hypothesize that esophageal stem cells become activated upon injury and are regulated by Transforming Growth Factor beta 1 (TGF?1), a known regulator of cell proliferation and differentiation. We established an in vitro model of quiescence using normal esophageal epithelial (STR) and oral (OKF6) cells treated with recombinant human TGF?1. Flow cytometry showed increases in cells arrested in G1/G0 phase of the cell cycle in TGF?1 treated cells for both cell lines (STR p(<)0.01, OKF6 p(<)0.05). EdU (5-ethynyl-2'-deoxyuridine) positive recovery cells indicated quiescence in both cell lines (p(<)0.01). Analysis of TGF?1 regulation of putative stem cell markers via western blot and qRT-PCR showed increases in ITGB1, PDPN and K15 as well as XPC, and MeCP2 in treated cells. To apply our in vitro findings, we performed immunohistochemistry staining on tissue microarrays. Proliferation marker Ki67 increased in disease progression from normal to inflammation to hyperplasia (p(<)0.001) while TGF?1 target markers decrease. Our data indicate that the onset of cancer-associated inflammation correlates with the loss of TGF?1 mediated stemness markers and increased basal proliferation suggesting cancer is a stem cell disease.
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Date Issued
2019
Identifier
CFE0007903, ucf:52754
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0007903
Downregulation in IFNGR1 increases suspectiblity to Mycobacterium avium subspecies paratuberculosis infection in Crohn's disease
Title
Downregulation in IFNGR1 increases suspectiblity to Mycobacterium avium subspecies paratuberculosis infection in Crohn's disease.
Creator
Htun, Zin Mar, Naser, Saleh, Andl, Claudia, Tigno-Aranjuez, Justine, University of Central Florida
Abstract / Description
BACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease (IBD) and has been associated with Mycobacterium avium subspecies paratuberculosis (MAP). MAP has been detected in stool, tissue and blood samples from patients with CD. Gamma interferon (?-IFN) is an inflammatory cytokine that plays a crucial role in killing intracellular pathogens like MAP, and its receptor (IFNGR1) mutations cause immunodeficiency and severe disseminated mycobacterial infections. The role of MAP in...
Show moreBACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease (IBD) and has been associated with Mycobacterium avium subspecies paratuberculosis (MAP). MAP has been detected in stool, tissue and blood samples from patients with CD. Gamma interferon (?-IFN) is an inflammatory cytokine that plays a crucial role in killing intracellular pathogens like MAP, and its receptor (IFNGR1) mutations cause immunodeficiency and severe disseminated mycobacterial infections. The role of MAP in association with IFNGR1 mutation in CD patients have not been investigated.METHODS: In this study, we investigated blood samples of 79 human subjects for MAP infection in association with IFNGR1 gene dysfunction. Samples were divided into 22 CD, 6 Ulcerative colitis (UC), 32 normal healthy and 19 non-inflammatory bowel disease (NIBD). Five variants of IFNGR1 single nucleotide polymorphisms (SNP) were investigated using Taqman Genotyping assay, then IFNGR1 expression measured by RT-PCR and serum IFNGR1 and ?-IFN levels were measured using ELISA. MAP infection was detected using nested PCR. RESULTS: Among 28 IBD patients, 4/6 (66.67%) of UC and 18/22 (81.82%) of CD are tested positive for at least one SNP homozygous minor form compared to 21.88% and 47.37%% in 32 healthy and 19 NIBD (P (<)0.05). IFNGR1 gene expression was downregulated 1.4-fold in IBD patients (P =0.07) and 1.7-fold downregulated in MAP positive IBD patients compared to MAP negative IBD patients (P=0.06). Serum IFNGR1 protein levels were downregulated 1.53-fold in IBD patients compared to normal, and 1.4-fold downregulated in MAP positive IBD patients compared to MAP negative IBD patients. MAP infection is more common in rs2234711 SNP positive patients (5/7 =71.42%) (P(<)0.05). Serum ?-IFN levels were not elevated in both groups.CONCLUSION: IFNGR1 SNP's, MAP infection and IFNGR1 downregulation were found in higher incidence in IBD, suggesting role of IFNGR1 in susceptibility of MAP infection in IBD patients.
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Date Issued
2017
Identifier
CFE0007121, ucf:51951
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0007121