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Expression of autophagy transcripts and proteins in the ocular lens suggests a role for autophagy in lens cell and cellular differentiation
Title
Expression of autophagy transcripts and proteins in the ocular lens suggests a role for autophagy in lens cell and cellular differentiation.
Creator
Mattucci, Lyndzie., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
The lens is an avascular organ that focuses light onto the retina where neural signals are transmitted to the brain and translated into images. Lens transparency is vital for maintaining function. The lens is formed through a transition from organelle-rich epithelial cells to organelle-free fiber cells. Lens cell differentiation, leading to the lack of organelles, provides an environment optimal for minimizing light scatter and maximizing the ability to focus light onto the retina. The...
Show moreThe lens is an avascular organ that focuses light onto the retina where neural signals are transmitted to the brain and translated into images. Lens transparency is vital for maintaining function. The lens is formed through a transition from organelle-rich epithelial cells to organelle-free fiber cells. Lens cell differentiation, leading to the lack of organelles, provides an environment optimal for minimizing light scatter and maximizing the ability to focus light onto the retina. The process responsible for orchestrating lens cell differentiation has yet to be elucidated. In recent years, data has emerged that led our lab to hypothesize that autophagy is likely involved in lens cell maintenance, cell differentiation, and maintenance of lens transparency. As a first step towards testing this hypothesis, we used RT-PCR, western blot analysis, immunohistochemistry, confocal microscopy, and next generation RNA-Sequencing (RNA-Seq) to examine autophagy genes expressed by the lens to begin mapping their lens function.
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Date Issued
2013
PURL
http://purl.flvc.org/fcla/dt/3360958
Subject Headings
Cell differentiation, Protein binding, Research, Cellular control mechanisms, Apoptosis
Format
Document (PDF)
Gene selection for sample sets with biased distribution
Title
Gene selection for sample sets with biased distribution.
Creator
Kamal, Abu Hena Mustafa., College of Engineering and Computer Science, Department of Computer and Electrical Engineering and Computer Science
Abstract/Description
Microarray expression data which contains the expression levels of a large number of simultaneously observed genes have been used in many scientific research and clinical studies. Due to its high dimensionalities, selecting a small number of genes has shown to be beneficial for many tasks such as building prediction models from the microarray expression data or gene regulatory network discovery. Traditional gene selection methods, however, fail to take the class distribution into the...
Show moreMicroarray expression data which contains the expression levels of a large number of simultaneously observed genes have been used in many scientific research and clinical studies. Due to its high dimensionalities, selecting a small number of genes has shown to be beneficial for many tasks such as building prediction models from the microarray expression data or gene regulatory network discovery. Traditional gene selection methods, however, fail to take the class distribution into the selection process. In biomedical science, it is very common to have microarray expression data which is severely biased with one class of examples (e.g., diseased samples) significantly less than other classes (e.g., normal samples). These sample sets with biased distributions require special attention from researchers for identification of genes responsible for a particular disease. In this thesis, we propose three filtering techniques, Higher Weight ReliefF, ReliefF with Differential Minority Repeat and ReliefF with Balanced Minority Repeat to identify genes responsible for fatal diseases from biased microarray expression data. Our solutions are evaluated on five well-known microarray datasets, Colon, Central Nervous System, DLBCL Tumor, Lymphoma and ECML Pancreas. Experimental comparisons with the traditional ReliefF filtering method demonstrate the effectiveness of the proposed methods in selecting informative genes from microarray expression data with biased sample distributions.
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Date Issued
2009
PURL
http://purl.flvc.org/FAU/186330
Subject Headings
Gene expression, Research, Methodology, Medical informatics, Apoptosis, Molecular aspects, DNA microarrays, Research
Format
Document (PDF)
A novel activity from an old compound: Manzamine A reduces the metastatic potential of AsPC-1 pancreatic cancer cells and sensitizes them to TRAIL-induced apoptosis
Title
A novel activity from an old compound: Manzamine A reduces the metastatic potential of AsPC-1 pancreatic cancer cells and sensitizes them to TRAIL-induced apoptosis.
Creator
Guzman, Esther A., Johnson, J. D., Linley, P. A., Wright, Amy E., Gunasekera, Sarath P.
Date Issued
2010
PURL
http://purl.flvc.org/FCLA/DT/3318907
Subject Headings
Pancreas--Cancer, Apoptosis, Sponges--Research, Marine natural products, Drug Discovery
Format
Document (PDF)
Engineered and natural TIMP mutations
Title
Engineered and natural TIMP mutations.
Creator
Hamze, Asmaa Bilal., Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
Tissue inhibitors of metalloproteinases (TIMPs) comprise a family of four proteins in humans that modulate the turnover of the extracellular matrix by regulating the activities of endopeptidases that catalyze its degradation, especially the matrix metalloproteinases (MMP). In general, the four TIMPs are broad-spectrum tight binding inhibitors of MMPs with individual differences in specificity. In this study, we attempted to understand the basis of such variation by using membrane type-1 MMP ...
Show moreTissue inhibitors of metalloproteinases (TIMPs) comprise a family of four proteins in humans that modulate the turnover of the extracellular matrix by regulating the activities of endopeptidases that catalyze its degradation, especially the matrix metalloproteinases (MMP). In general, the four TIMPs are broad-spectrum tight binding inhibitors of MMPs with individual differences in specificity. In this study, we attempted to understand the basis of such variation by using membrane type-1 MMP (MT1-MMP) as a model, since it is inefficiently inhibited by TIMP-1 in contrast with the other TIMPs. We designed and engineered mutations in the N-domain of TIMP-1, based on current knowledge of TIMP interactions. By measuring inhibition levels of each mutant against several MMPs, including MT1-MMP, we were able to obtain a triple mutant with an vii improved affinity for MT1-MMP., Our results, along with previous data, confirm that multiple residues in the critical interface segments between TIMPs and MMPs, namely at positions 2, 4, 5, 6, and 98, are key in determining the basic interaction between the two molecules. The second part of this work focused on naturally occurring mutations in TIMP-3 which cause an early form of macular degeneration called Sorsby's Fundus Dystrophy (SFD). The TIMP-3 mutants identified so far share certain features but the mechanism by which they result in macular disease is not yet understood. As an initial step, we expressed recombinant TIMP-3 carrying a truncation mutation, glutamic acid 139 to a stop codon (E139X), and assessed its activity towards representative MMPs and tumor necrosis factor-(Sa (Bconverting enzyme, another metalloproteinase normally inhibited by TIMP-3. Our results indicate that this mutation does not impair the inhibitory activity of TIMP-3., Expression of this mutant in mammalian retinal cells revealed a difference in localization between wild-type and E139X mutant TIMP-3. Therefore, we concluded that the SFD mutations may actually influence the processing and/or binding properties of TIMP-3 in the retina.
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Date Issued
2008
PURL
http://purl.flvc.org/FAU/186296
Subject Headings
Proteolytic enzymes, Extracellular matrix proteins, Metalloproteinases, Inhibitors, Apoptosis, Retinal degeneration, Research
Format
Document (PDF)
Potential therapies and neuroprotective cascades in anoxia tolerant freshwater turtle Trachemys scripta ellegans
Title
Potential therapies and neuroprotective cascades in anoxia tolerant freshwater turtle Trachemys scripta ellegans.
Creator
Nayak, Gauri., Charles E. Schmidt College of Science, Department of Biomedical Science
Abstract/Description
Mammalian neurons exhibit extreme sensitivity to oxygen deprivation and undergo rapid and irreversible degeneration when oxygen supply is curtailed. Though several neuroprotective pathways are activated during oxygen deprivation, their analyses are masked by the complex series of pathological events which are triggered simultaneously. Such events can be analyzed in the anoxia tolerant fresh water turtle, which can inherently survive the conditions of oxygen deprivation and post-anoxic...
Show moreMammalian neurons exhibit extreme sensitivity to oxygen deprivation and undergo rapid and irreversible degeneration when oxygen supply is curtailed. Though several neuroprotective pathways are activated during oxygen deprivation, their analyses are masked by the complex series of pathological events which are triggered simultaneously. Such events can be analyzed in the anoxia tolerant fresh water turtle, which can inherently survive the conditions of oxygen deprivation and post-anoxic reoxygenation without brain damage. It is likely in such a model that modulation of a particular molecular pathway is adaptive rather than pathological. The major objective behind this study was to analyze the intracellular signaling pathways mediating the protective effects of adenosine, a potential neuromodulator, and its effect on cell survival by influencing the key prosurvival proteins that prevent apoptosis. In vivo and in vitro studies have shown that adenosine acts as a neuroprotective metabolite and its action can be duplicated or abrogated using specific agonist and antagonists. Stimulating the adenosine receptors using selective A1 receptor agonist N6-cyclopentyladenosine (CPA) activated the presumed prosurvival ERK and P13-K/AKT cascade promoting cell survival, and suppression of the receptor using the selective antagonist DPCPX (8- cyclopentyl-1,3-dipropylxanthine) activated the prodeath JNK and P38 pathways. The complex regulation of the MAPK's/AKT signaling cascades was also analyzed using their specific inhibitors. The inhibiton of the ERK and AKT pathway increased cell death, indicating a prosurvival role, whereas inhibiton of the JNK and p38 pathway increased cell survival in this model. In vitro studies have also shown a high Bcl-2/BAX ratio during anoxia and reoxygenation, indicating a strong resistance to cell death via apoptosis., Silencing of the anti-apoptotic Bcl-2 gene using specific siRNA upregulated levels of prodeath BAX, thus altering the Bcl-2/BAX ratio and elevating cleaved Caspase-3 levels leading to increased cell death. Another promising neuroprotective target which we analyzed was Neuroglobin, which was induced during oxygen crisis and silencing this gene indicated that its plays a major role in modulation of ROS. This study strongly emphasizes the advantages of an alternate animal model in elucidating neuroprotective mechanisms and revealing novel therapeutic targets which could eventually help clinicians to design new stroke therapies based on naturally tolerant organisms.
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Date Issued
2009
PURL
http://purl.flvc.org/FAU/186762
Subject Headings
Turtles, Physiology, Adenosine, Receptors, Cellular signal transduction, Molecular neurobiology, Apoptosis, Research, Cellular control mechanisms
Format
Document (PDF)
Integrin αVβ5-mediated Removal Of Apoptotic Cell Debris By The Eye Lens And Its Inhibition By UV-light Exposure
Title
Integrin αVβ5-mediated Removal Of Apoptotic Cell Debris By The Eye Lens And Its Inhibition By UV-light Exposure.
Creator
Bakina, Olga, Kantorow, Marc, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
The lens is a crystallin tissue of the anterior part of the eye that focuses light onto the retina. Aged-related cataract, which is the result of loss of lens transparency, is the most common cause of blindness in the world. Being constantly exposed to UV-light, lens is significantly affected by its UVA spectrum. UV-light exposure has been shown to result in apoptosis of lens cells which can lead to cataract formation. This suggests the need for molecular mechanisms to remove apoptotic debris...
Show moreThe lens is a crystallin tissue of the anterior part of the eye that focuses light onto the retina. Aged-related cataract, which is the result of loss of lens transparency, is the most common cause of blindness in the world. Being constantly exposed to UV-light, lens is significantly affected by its UVA spectrum. UV-light exposure has been shown to result in apoptosis of lens cells which can lead to cataract formation. This suggests the need for molecular mechanisms to remove apoptotic debris from the lens. In the set of experiments it was proven that integrin αvβ5-mediated pathway is involved in phagocytosis of apoptotic cell debris in the ocular lens, thus contributing to its homeostasis. Additionally, it was shown that exposure to UV-light plays role in cataract formation by influencing integrin αvβ5-mediated phagocytosis function.
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Date Issued
2016
PURL
http://purl.flvc.org/fau/fd/FA00004568
Subject Headings
Eye x Diseases--Research., Retinal degeneration., Cellular control mechanisms., Apoptosis
Format
Document (PDF)
The Single Minded 2 Gene (SIM2) and Cancer: Harnessing Micro-Array Data to Facilitate Pathway Discovery and Validation
Title
The Single Minded 2 Gene (SIM2) and Cancer: Harnessing Micro-Array Data to Facilitate Pathway Discovery and Validation.
Creator
Aleman, Mireille J., Narayanan, Ramaswamy, Florida Atlantic University
Abstract/Description
A Down's Syndrome related Single Minded 2 gene (SIM2), previously known to be associated with Trisomy 21 was predicted by bioinformatics to be colon cancer specific. In previous work from the laboratory using a patient tissue repository, an isoform of this gene, short form (SIM2-s) was shown to be colon cancer specific. Inhibition of SIM2-s expression by antisense technology resulted in cancer-cell specific apoptosis within 24 hours. Microarray-based gene expression profiling of the antisense...
Show moreA Down's Syndrome related Single Minded 2 gene (SIM2), previously known to be associated with Trisomy 21 was predicted by bioinformatics to be colon cancer specific. In previous work from the laboratory using a patient tissue repository, an isoform of this gene, short form (SIM2-s) was shown to be colon cancer specific. Inhibition of SIM2-s expression by antisense technology resulted in cancer-cell specific apoptosis within 24 hours. Microarray-based gene expression profiling of the antisense-treated colon cancer cells provided a fingerprint of genes involving key cell cycle, apoptosis, DNA damage and differentiation genes. Taking hints from the microarray database, experiments were initiated to decipher the molecular mechanism underlying the cancer specific function of the SIM2-s gene. Using an isogenic cell system, apoptosis was found to be dependent on DNA damage and repair gene, GADD45-a. Further, key pathways including p38 MAP kinase (MAPK) and specific caspases were essential for apoptosis. Programmed cell death was not dependant on cell cycle and was preceded by the induction of terminal differentiation. To clarify whether SIM2-s function is a critical determinant of differentiation, stable transfectants of SIM2-s were established in a murine adipocytic cell line (3T3-L 1 ). SIM2-s overexpression caused a pronounced block of differentiation of the pre-adipocytes into mature adipocytes. A study of the differentiation pathway in 3T3-L 1 cells suggested that this block occurs early on in the cascade. These results supported the starting premise that SIM2-s is a critical mediator of cell differentiation. To clarify whether the SIM2-s gene has transforming potential, the SIM2-s gene was overexpressed in the NIH3T3 murine fibroblast cell line. The cells expressing the human SIM2-s gene exhibited shorter doubling time, abrogation of growth serum requirement, greater cell number at saturation density and focus formation. In vivo tumorigenicity assays showed tumor formation with long latency. These results provide strong evidence for the role of SIM2-s gene in tumor cell growth and differentiation, and validate drug therapy use for the gene.
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Date Issued
2007
PURL
http://purl.flvc.org/fau/fd/FA00000845
Subject Headings
Cancer--Genetic aspects, DNA microarrays--Diagnostic use, Apoptosis--Molecular aspects, Medical informatics, Gene expression--Research--Methodology
Format
Document (PDF)
Molecular pathway identification using microarray technology
Title
Molecular pathway identification using microarray technology.
Creator
Tress, Matthew David., Florida Atlantic University, Narayanan, Ramaswamy
Abstract/Description
Harnessing the human genome using bioinformatics lead to the discovery of a highly cancer-selective gene, Single Minded 2 gene (SIM2). An isoform of the SIM2 gene, the short-form (SIM2-s), was shown to be specific to colon, pancreas, and prostate tumors. Antisense inhibition of SIM2-s in a colon carcinoma derived cell line (RKO) caused inhibition of gene expression, growth inhibition and apoptosis in vitro and in nude mice tumorigenicity models. To understand the mechanism of Sim2-s antisense...
Show moreHarnessing the human genome using bioinformatics lead to the discovery of a highly cancer-selective gene, Single Minded 2 gene (SIM2). An isoform of the SIM2 gene, the short-form (SIM2-s), was shown to be specific to colon, pancreas, and prostate tumors. Antisense inhibition of SIM2-s in a colon carcinoma derived cell line (RKO) caused inhibition of gene expression, growth inhibition and apoptosis in vitro and in nude mice tumorigenicity models. To understand the mechanism of Sim2-s antisense, the antisense treated RKO colon cancer cells were monitored for genome wide expression using Affymetrix GeneChipRTM technology. A list of apoptosis related genes was generated using GeneSpringRTM software. Select GeneChip RTM output was validated by Quantitative RT-PCR. Relevance of a key gene, Growth arrest and DNA damage inducible (GADD45a), in the SIM2-s pathway was established. These results will provide a basis for the future experiments to understand the mechanism underlying Sim2-s activation in specific tumors.
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Date Issued
2004
PURL
http://purl.flvc.org/fcla/dt/13146
Subject Headings
Medical informatics, DNA microarrays--Diagnostic use, Cancer--Genetic aspects, Apoptosis--Molecular aspects, Human genetics--Variation, Gene expression--Research--Methodology
Format
Document (PDF)