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Hypoxia and Chromatin Remodeling: Essential Regulators of Ocular Lens Cell Differentiation
Title
Hypoxia and Chromatin Remodeling: Essential Regulators of Ocular Lens Cell Differentiation.
Creator
Disatham, Joshua, Kantorow, Marc, Florida Atlantic University, Department of Biological Sciences, Charles E. Schmidt College of Science
Abstract/Description
The ocular lens is comprised of an epithelial cell population that undergoes a continuous process of cellular remodeling and differentiation to form elongated transparent fiber cells. This lens differentiation process is hallmarked by the complete elimination of organelles at the center of the lens, elongation of lens fiber cells, and production of lens fiber-cell specific crystallin proteins to form the mature functional structure of the transparent ocular lens. To date, our understanding of...
Show moreThe ocular lens is comprised of an epithelial cell population that undergoes a continuous process of cellular remodeling and differentiation to form elongated transparent fiber cells. This lens differentiation process is hallmarked by the complete elimination of organelles at the center of the lens, elongation of lens fiber cells, and production of lens fiber-cell specific crystallin proteins to form the mature functional structure of the transparent ocular lens. To date, our understanding of the mechanisms that drive the lens differentiation process is incomplete. This dissertation sought to elucidate the potential roles of both hypoxia and epigenetic chromatin remodeling processes as novel regulators of lens differentiation. The lens lacks a direct blood supply and thus resides in a hypoxic microenvironment. Previous studies revealed the presence of a decreasing oxygen gradient in the region of the lens where cellular remodeling and organelle elimination occur to form mature transparent lens fiber cells. Thus we hypothesized that the hypoxic environment of the lens itself, was required to induce gene expression changes to drive the lens differentiation process. We utilized a multimoics analysis combining CUT&RUN and RNAseq high-throughput sequencing technologies to identify a role for the hypoxia-inducible transcription factor HIF1a as a novel regulator of lens gene expression during lens differentiation.
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Date Issued
2022
PURL
http://purl.flvc.org/fau/fd/FA00013985
Subject Headings
Hypoxia, Chromatin, Cell Differentiation, Eye
Format
Document (PDF)
DEVELOPMENT OF A HIFI-Α LENS SPECIFIC KNOCKOUT MOUSE AS A MODEL FOR HYPOXIA DRIVEN LENS DIFFERENTIATION
Title
DEVELOPMENT OF A HIFI-Α LENS SPECIFIC KNOCKOUT MOUSE AS A MODEL FOR HYPOXIA DRIVEN LENS DIFFERENTIATION.
Creator
Adele, Adedamola, Kantorow, Marc, Florida Atlantic University, Department of Biomedical Science, Charles E. Schmidt College of Medicine
Abstract/Description
During eye lens development the lens receives oxygen from a network of capillaries that comprise of the tunica vasculosa lentis and the anterior pupillary membrane. In development there is regression of this capillaries with the vitreous and aqueous humor, which is the lens only source of oxygen, leaving the lens in low oxygen state. The lens contains a decreasing oxygen gradient from the surface to the core that parallels the differentiation of immature surface epithelial cells into mature...
Show moreDuring eye lens development the lens receives oxygen from a network of capillaries that comprise of the tunica vasculosa lentis and the anterior pupillary membrane. In development there is regression of this capillaries with the vitreous and aqueous humor, which is the lens only source of oxygen, leaving the lens in low oxygen state. The lens contains a decreasing oxygen gradient from the surface to the core that parallels the differentiation of immature surface epithelial cells into mature core transparent fiber cells. These properties of the lens suggest a potential role for hypoxia and the master regulator of the hypoxic response, hypoxia-inducible transcription factor 1 alpha (HIF1a), in the regulation of genes required for lens fiber cell differentiation, structure, and transparency. Previous studies by our lab discovered the HIF1a-dependent gene expression patterns of lens genes by utilizing a Multiomics approach that integrated analysis from CUT&RUN, RNA-seq, and ATACseq. Additionally, our lab also established a hypoxia and HIF1a-dependent mechanism for the non-nuclear organelle degradation process required to form mature transparent fiber cells.
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Date Issued
2023
PURL
http://purl.flvc.org/fau/fd/FA00014167
Subject Headings
Cell differentiation, Lens, Crystalline, Eye lens
Format
Document (PDF)
THE EFFECT OF S81 WITHIN THE MINIMAL ESSENTIAL REGION (MER) OF THE BNIP3L PROTEIN IN ACTIVATING ORGANELLE DEGRADATION TO DRIVE FIBER LENS DIFFERENTIATION
Title
THE EFFECT OF S81 WITHIN THE MINIMAL ESSENTIAL REGION (MER) OF THE BNIP3L PROTEIN IN ACTIVATING ORGANELLE DEGRADATION TO DRIVE FIBER LENS DIFFERENTIATION.
Creator
Yang, Judy, Kantorow, Marc, Florida Atlantic University, Department of Biomedical Science, Charles E. Schmidt College of Medicine
Abstract/Description
Lens differentiation begins with epithelial cells that undergo the process of cellular differentiation and remodelling into fiber cells (Bassnet et al., 2011; Menko 2002; Wride, 2011) that then will undergo terminal remodelling processes to eliminate their cellular organelles to achieve mature lens structure and transparency. We sought to determine if Serine 81, within the minimal essential region (MER) of the BNIP3L protein, is required for organelle elimination. Previous studies have shown...
Show moreLens differentiation begins with epithelial cells that undergo the process of cellular differentiation and remodelling into fiber cells (Bassnet et al., 2011; Menko 2002; Wride, 2011) that then will undergo terminal remodelling processes to eliminate their cellular organelles to achieve mature lens structure and transparency. We sought to determine if Serine 81, within the minimal essential region (MER) of the BNIP3L protein, is required for organelle elimination. Previous studies have shown that levels of phosphorylated P38 MAPK and ERK ½ peaked in the same region as phosphorylated S81 BNIP3L levels, the equatorial epithelium, where organelle degradation is initiated. The use of specific inhibitors of P38 MAPK (SB203580) or ERK ½ (U0126 or PD99089) and P38 MAPK activator Ansiomycin will be used to determine if P38 MAPK or ERK ½ phosphorylates BNIP3L at S81 to induce mitophagy of mitochondria, endoplasmic reticulum, and Golgi apparatus.
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Date Issued
2023
PURL
http://purl.flvc.org/fau/fd/FA00014166
Subject Headings
Lens, Crystalline, Cell differentiation, Eye lens
Format
Document (PDF)
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)
Regulation of growth by TGF-B in Drosophila
Title
Regulation of growth by TGF-B in Drosophila.
Creator
Gesualdi, Scott C., Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
Key to our understanding of growth regulation in Drosophila would be discovering a ligand that could regulate steroid synthesis. Activins are involved in regulating steroid hormone release in vertebrates. In invertebrates, they most likely function to keep ecdysone levels low to allow the larvae more time to achieve critical weight in order to initiate the metamorphic process. TGF-B(Transforming Growth Factor Beta) is a family of cytokine growth factors. We find that two members of the TGF-B...
Show moreKey to our understanding of growth regulation in Drosophila would be discovering a ligand that could regulate steroid synthesis. Activins are involved in regulating steroid hormone release in vertebrates. In invertebrates, they most likely function to keep ecdysone levels low to allow the larvae more time to achieve critical weight in order to initiate the metamorphic process. TGF-B(Transforming Growth Factor Beta) is a family of cytokine growth factors. We find that two members of the TGF-B signaling pathway Drosophila Activin (dACT) and Activin-like ligand Dawdle (DAW) signal through the type I receptor Baboon (BABO) and the type II receptor PUNT to primarily activate the transcription factor dSMAD2 and MAD to a lesser extent. One transcription factor brinker (brk) appears to be central to dACT signaling., In wings dACT signaling is necessary to promote growth however, dACT is not expressed in wings suggesting that dACT is provided through the endocrine system. One possible target tissue of dACT signaling is the ring gland (RG), which synthesizes and secretes the steroid hormone ecdysone (E). Consistent with this idea, using the UAS/GAL-4 system, we find that over-expression of the TGF-B ligand dACT with the neuroendocrine driver 386Y-GAL4 results in an increase in the size of flies. Surprisingly, when we increase the dose with two copies of dACT, it decreases the size of flies also indicating non-autononomous effects. We find that overexpression of the activated form of the dACT type I receptor Baboon (BABO) or brk with the ring gland specific driver phm-GAL4 results in developmental arrest of larvae that stay small and never pupate. The developmental arrest can be overcome by feeding larvae E, suggesting that dACT represses E through brk. These results suggest a model where dACT signaling activates brk which inhibits E. We picked three cytochrome P450 enzymes: phantom (PHM), disembodied (DIS) and spookier (SPKR)., PHM is not regulated by any component in the dACT signaling pathway however, we find DIS and SPKR are down-regulated through brk. MAD and dSmad2 bind to a Smad binding site and MAD out-competes dSMAD2. We find no evidence that Drosophila insulin-like peptides (DILPS)/PI3- Kinase or Ras signal through the dActivin signaling pathway.
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Date Issued
2009
PURL
http://purl.flvc.org/FAU/228773
Subject Headings
Cell differentiation, Developmental genetics, Integrins, Cellular control mechanisms
Format
Document (PDF)
REGULATION OF CASPASE-3 ACTIVATION BY PHOSPHORYALTED Ab-CRYSTALLIN AND ITS ROLE IN DIFFERENTIATION
Title
REGULATION OF CASPASE-3 ACTIVATION BY PHOSPHORYALTED Ab-CRYSTALLIN AND ITS ROLE IN DIFFERENTIATION.
Creator
Cherubin, Patrice, Kantorow, Marc, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
The lens is responsible for focusing light into the retina. It accomplishes this through its maturation from an epithelial cell into a fiber cell. A large amount of research has been done on cellular differentiation. Nevertheless, we still lack knowledge on many different aspects of differentiation, including a complete theory on the mechanism behind differentiation. Due to the lens’ unique structure and cell types, this is an ideal model for studying differentiation. Our research has shown...
Show moreThe lens is responsible for focusing light into the retina. It accomplishes this through its maturation from an epithelial cell into a fiber cell. A large amount of research has been done on cellular differentiation. Nevertheless, we still lack knowledge on many different aspects of differentiation, including a complete theory on the mechanism behind differentiation. Due to the lens’ unique structure and cell types, this is an ideal model for studying differentiation. Our research has shown that αB crystallin, a small heat shock protein, is able to modulate cytochrome C levels and protect the mitochondria under oxidative stress. Also, cytochrome C release is often followed by caspase 3 activation. In addition, research has shown that low levels of caspase 3 activation is essential in driving differentiation. My work examined if αB crystallin could modulate cytochrome C to lower caspase 3 levels to allow for differentiation rather than apoptosis.
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Date Issued
2019
PURL
http://purl.flvc.org/fau/fd/FA00013293
Subject Headings
Caspase 3, Cell differentiation, Crystallins, Phosphorylation, Cytochromes C
Format
Document (PDF)
Do Fiddler Crab Larvae Show Phenotypic Plasticity?
Title
Do Fiddler Crab Larvae Show Phenotypic Plasticity?.
Creator
Christopher, Catherine E., Salmon, Michael, Florida Atlantic University
Abstract/Description
Larval release by adult fiddler crabs occurs during the ebbing tides, but its timing relative to the day-night and tidal amplitude cycles depends upon tidal form (e.g., shows phenotypical plasticity). Crabs (Uca thayeri) from Florida's East Coast are exposed to semidiurnal tides and release their larvae at night, whereas crabs from Florida's West Coast exposed to mixed tides release their larvae during the afternoon. The purpose of this study was to determine whether the larvae could hatch at...
Show moreLarval release by adult fiddler crabs occurs during the ebbing tides, but its timing relative to the day-night and tidal amplitude cycles depends upon tidal form (e.g., shows phenotypical plasticity). Crabs (Uca thayeri) from Florida's East Coast are exposed to semidiurnal tides and release their larvae at night, whereas crabs from Florida's West Coast exposed to mixed tides release their larvae during the afternoon. The purpose of this study was to determine whether the larvae could hatch at times other than those correlated with the tidal form at their location. Clusters of eggs at similar stages of development, 24-72 h in advance of release, were reciprocally transferred between females from each coast. Release ofboth the transferred larvae and maternal clutch occurred synchronously, and at the time dictated by the female's tidal regime. These results suggest that larvae are phenotypically plastic with respect to hatching time and can either delay (West coast) or advance (East coast) their response to release signals from females.
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Date Issued
2007
PURL
http://purl.flvc.org/fau/fd/FA00000733
Subject Headings
Cell differentiation, Adaptation (Biology), Evolution (Biology), Phenotypic plasticity
Format
Document (PDF)
Tissue Protection and Cell Death Pathways in Myocardial Ischemia
Title
Tissue Protection and Cell Death Pathways in Myocardial Ischemia.
Creator
Rickaway, Zach T., Prentice, Howard, Florida Atlantic University
Abstract/Description
The excess generation of Reactive oxygen species (ROS) can damage cell components and disrupt cellular functions. Methionine in proteins is easily oxidized by ROS and converted to methionine sulfoxide. The enzyme peptide Methionine Sulfoxide Reductase reduces methionine sulfoxide back to methionine. We report here that MsrA over expression in rat cardiac myocytes prevents damage from ROS and increases cell viability after hypoxic/reoxygenation events. The nonsteroidal anti-inflamatory drug ...
Show moreThe excess generation of Reactive oxygen species (ROS) can damage cell components and disrupt cellular functions. Methionine in proteins is easily oxidized by ROS and converted to methionine sulfoxide. The enzyme peptide Methionine Sulfoxide Reductase reduces methionine sulfoxide back to methionine. We report here that MsrA over expression in rat cardiac myocytes prevents damage from ROS and increases cell viability after hypoxic/reoxygenation events. The nonsteroidal anti-inflamatory drug (NSAID) sulindac contains a methyl sulfoxide moiety that can scavenge ROS. Sulindac can be reduced by MsrA and contribute as an antioxidant in the cell. Our results demonstrate that 1 OOuM sulindac can reduce cell death in rat cardiac myocytes during hypoxia/reoxygenation, and ischemia/reperfusion in Langendorf[ perfusions. The BNIP proteins are pro-apoptotic members of the Bcl-2 family of apoptosis regulating proteins. Hypoxia/acidosis stabilizes BNIP-3 and increases its association with the mitochondria, causing the release of cytochrome C and cell death. We report the retrograde perfusion Langendorffmodel is inconclusive in mouse hearts.
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Date Issued
2006
PURL
http://purl.flvc.org/fau/fd/FA00000820
Subject Headings
Mitochondrial pathology, Heart--Pathophysiology, Apoptosis, Cell differentiation
Format
Document (PDF)
Understanding the role of transgenic catalase in T-cell development in murine-based studies
Title
Understanding the role of transgenic catalase in T-cell development in murine-based studies.
Creator
Smith, Richard M., Harriet L. Wilkes Honors College
Abstract/Description
The thymus provides a unique microenvironment that facilitates T lymphocytes differentiation and maturation. However, the thymus atrophies after puberty which leads to an overall expression of metabolism gene pathways and low gene expression of certain peroxide scavenger enzymes such as catalase in thymic stromal compartments. From this data, we postulate that thymic stromal cells are highly susceptible to oxidative damage. We utilized a transgenic mice model overexpressing human catalase...
Show moreThe thymus provides a unique microenvironment that facilitates T lymphocytes differentiation and maturation. However, the thymus atrophies after puberty which leads to an overall expression of metabolism gene pathways and low gene expression of certain peroxide scavenger enzymes such as catalase in thymic stromal compartments. From this data, we postulate that thymic stromal cells are highly susceptible to oxidative damage. We utilized a transgenic mice model overexpressing human catalase targeted to the mitochondria (mCat) to test our hypothesis that gerater oxidative protection should lower the degree of thymus atrophy. Our experiment focused on a direct comparison of organ weights (thymus, kidney, lymph nodes, spleen and heart), cellularity and histology between transgenic and wildtype mice. We found that mCat had selective increases in thymus size.
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Date Issued
2012
PURL
http://purl.flvc.org/FAU/3359325
Subject Headings
T cells, Differentiation, Developmental genetics, Gene expression, Human cell culture, Thymus, Physiology
Format
Document (PDF)
Relationships of fibroblast growth factor 21 with inflammation and insulin resistance in response to acute exercise in obese individuals
Title
Relationships of fibroblast growth factor 21 with inflammation and insulin resistance in response to acute exercise in obese individuals.
Creator
Slusher, Aaron L., Huang, Chun-Jung, Florida Atlantic University, College of Education, Department of Exercise Science and Health Promotion
Abstract/Description
Obesity is associated with elevated levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), contributing to systemic insulin resistance. Fibroblast growth factor 21 (FGF21) is a vital metabolic and inflammatory regulator, however circulating FGF21 concentrations are elevated in obese individuals. Acute aerobic exercise increases systemic FGF21 in normal-weight individuals, however the effect of acute aerobic exercise on plasma FGF21 response and...
Show moreObesity is associated with elevated levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), contributing to systemic insulin resistance. Fibroblast growth factor 21 (FGF21) is a vital metabolic and inflammatory regulator, however circulating FGF21 concentrations are elevated in obese individuals. Acute aerobic exercise increases systemic FGF21 in normal-weight individuals, however the effect of acute aerobic exercise on plasma FGF21 response and the relationships with inflammation (IL-6 and TNF-α), insulin resistance, and energy expenditure in obese individuals is unknown. Following 30 minutes of treadmill running at 75% VO2max, plasma FGF21 response, as indicated by area-under-the-curve “with respect to increase” (AUCi) analyses, was attenuated in 12 obese compared to 12 normalweight subjects. Additionally, FGF21 AUCi positively correlated with glucose AUCi, total relative energy expenditure, and relative VO2max, suggesting that cardiorespiratory fitness levels may predict FGF21 response, contributing to the enhanced regulation of glucose and energy metabolism.
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Date Issued
2014
PURL
http://purl.flvc.org/fau/fd/FA00004229, http://purl.flvc.org/fau/fd/FA00004229
Subject Headings
Fibroblast growth factor., Cell differentiation., Cellular signal transduction., Obesity--Health aspects., Metabolic syndrome--Pathophysiology.
Format
Document (PDF)
Highwire coordinates synapse formation and maturation by regulating both a map kinase cascade and the ability of the axon to respond to external cues in the giant fiber system of Drosophila Melanogaster
Title
Highwire coordinates synapse formation and maturation by regulating both a map kinase cascade and the ability of the axon to respond to external cues in the giant fiber system of Drosophila Melanogaster.
Creator
Borgen, Melissa A., Murphey, Rodney K., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
The ubiquitin ligase Highwire is responsible for cell-autonomously promoting synapse formation in the Drosophila Giant Fiber system. highwire mutants show defects in synaptic function and extra branching at the axon terminal, corresponding to transient branching that occur in the course of giant synapse formation during metamorphosis. The MAP kinase pathway, including Wallenda and JNK/Basket, plus the transcription factor Jun, act to suppress synaptic function and axon pruning in a dosage...
Show moreThe ubiquitin ligase Highwire is responsible for cell-autonomously promoting synapse formation in the Drosophila Giant Fiber system. highwire mutants show defects in synaptic function and extra branching at the axon terminal, corresponding to transient branching that occur in the course of giant synapse formation during metamorphosis. The MAP kinase pathway, including Wallenda and JNK/Basket, plus the transcription factor Jun, act to suppress synaptic function and axon pruning in a dosage sensitive manner, suggesting different molecular mechanisms downstream of the MAP kinase pathway govern function and pruning. A novel role for Highwire is revealed, regulating the giant fiber axon’s ability to respond to external cues regulated by Fos. When expression of the transcription factor Fos is disrupted in the post-synaptic TTMn or surrounding midline glia of highwire mutants, the giant fiber axons show a marked increase in axon overgrowth and midline crossing. However, synaptic function is rescued by the cell nonautonomous manipulation of Fos, indicating distinct mechanisms downstream of Highwire regulating synaptic function and axon morphology.
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Date Issued
2014
PURL
http://purl.flvc.org/fau/fd/FA00004081, http://purl.flvc.org/fau/fd/FA00004081
Subject Headings
Cell differentiation, Cellular control mechanisms, Cellular signal transduction, Drosophila melanogaster -- Cytogenetics, Gene expression, Genetic transcription
Format
Document (PDF)
Differential expression of cardiac troponin T isoforms in normal and cardiac non-function mutant axolotl hearts
Title
Differential expression of cardiac troponin T isoforms in normal and cardiac non-function mutant axolotl hearts.
Creator
Sferrazza, Gian Franco., Florida Atlantic University, Lemanski, Larry F.
Abstract/Description
A recessive mutant gene, termed "c", for cardiac non-function in the Mexican axolotl, Ambystoma mexicanum, is responsible for the failure of myofibrillogenesis in cardiac nonfunction mutant embryonic hearts. Animals that are homozygous for the mutation (c/c) fail to develop beating hearts and consequently die. Thus, the Mexican axolotl has been a useful animal model to study embryonic heart development. Recently, the cardiac troponin T (cTnT) gene, along with three additional shorter isoforms...
Show moreA recessive mutant gene, termed "c", for cardiac non-function in the Mexican axolotl, Ambystoma mexicanum, is responsible for the failure of myofibrillogenesis in cardiac nonfunction mutant embryonic hearts. Animals that are homozygous for the mutation (c/c) fail to develop beating hearts and consequently die. Thus, the Mexican axolotl has been a useful animal model to study embryonic heart development. Recently, the cardiac troponin T (cTnT) gene, along with three additional shorter isoforms of the gene, were cloned from normal embryonic hearts. These isoforms are believed to be the alternately spliced forms of the full length gene. One of the isoforms cloned is missing a cardiac-specific exon. Real-time PCR reveals that homozygous recessive mutant embryos (c/c) exhibit a lower transcription level of the cTnT gene than wildtype animals (+/+ or +/c). Expression levels of each of the isoforms are compared in normal and mutant hearts using quantitative real-time PCR.
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Date Issued
2006
PURL
http://purl.flvc.org/fcla/dt/13320
Subject Headings
Vertebrates--Embryology--Methodology, Muscles--Molecular aspects, Gene expression, Cell differentiation
Format
Document (PDF)
Posttranscriptional regulation of tropomyosin expression by myofibril inducing RNA (MIR) during axolotl embryonic heart development
Title
Posttranscriptional regulation of tropomyosin expression by myofibril inducing RNA (MIR) during axolotl embryonic heart development.
Creator
Jia, Pingping, Florida Atlantic University, Lemanski, Larry F., Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
A naturally-occurring recessive lethal mutation in axolotls, Ambystoma mexicanum, is an intriguing model for studying tropomyosin expression regulation. Homozygous embryos(c/c) form hearts that are deficient in tropomyosin, lack organized myofibrils and fail to beat. Previous studies have shown that a non-coding RNA gene, MIR (Myofibril Inducing RNA), is sufficient to rescue the non-beating homozygous recessive mutant hearts by promoting sarcomeric tropomyosin expression that leads to...
Show moreA naturally-occurring recessive lethal mutation in axolotls, Ambystoma mexicanum, is an intriguing model for studying tropomyosin expression regulation. Homozygous embryos(c/c) form hearts that are deficient in tropomyosin, lack organized myofibrils and fail to beat. Previous studies have shown that a non-coding RNA gene, MIR (Myofibril Inducing RNA), is sufficient to rescue the non-beating homozygous recessive mutant hearts by promoting sarcomeric tropomyosin expression that leads to formation of organized myofibrils and beating hearts. Real time RT-PCR reveals that mutant hearts express the same level mRNA of the alpha-tropomyosin and TM4 type tropomyosin (ATmC-3) gene as normal embryonic hearts. These genes show no differences with regard to the splicing patterns of normal and mutant. Using protease inhibitor LLnL and E-64d treatments and two-dimensional Western blots of normal and mutant hearts, it is found that mutant hearts express all tropomyosin protein isoforms as normal hearts but protein expression are at low levels. These studies suggest that there is a failure in the translational or posttranslational control mechanisms for tropomyosin protein synthesis in cardiac mutant axolotl hearts during development.
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Date Issued
2006
PURL
http://purl.flvc.org/fcla/dt/13380
Subject Headings
Medical genetics, Molecular biology, Cell differentiation, Gene expression, Axolotls--Development, Heart--Growth--Molecular aspects
Format
Document (PDF)
Functional analysis of Drosophila and human follistatin domains and their role in growth inhibition
Title
Functional analysis of Drosophila and human follistatin domains and their role in growth inhibition.
Creator
Shah, Ripal., Florida Atlantic University, Haerry, Theodor E.
Abstract/Description
Follistatin (FS) proteins are highly conserved inhibitors of Activins, members of the Transforming Growth Factor beta (TGF-beta) family, which play prominent roles in patterning and cell proliferation, and can contribute to tumor formation. Comparison of FS from Drosophila (dFS) and humans (hFS) in flies shows that hFS is less active. The goal of this thesis is to test three possible mechanisms: dFS might be more stable and turn over at a lower rate, exhibit a stronger affinity for ligands,...
Show moreFollistatin (FS) proteins are highly conserved inhibitors of Activins, members of the Transforming Growth Factor beta (TGF-beta) family, which play prominent roles in patterning and cell proliferation, and can contribute to tumor formation. Comparison of FS from Drosophila (dFS) and humans (hFS) in flies shows that hFS is less active. The goal of this thesis is to test three possible mechanisms: dFS might be more stable and turn over at a lower rate, exhibit a stronger affinity for ligands, or diffuse less because of stronger interaction with the extracellular matrix. We generated chimeric proteins of dFS and hFS by exchanging individual protein domains. Our results suggest that the increased activity is likely due to ligand binding. Based on the recent structure of the hFS-Activin complex, we speculate that stronger interactions with heparin sulfate in the extracellular matrix may also contribute to the increased activity of dFS.
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Date Issued
2005
PURL
http://purl.flvc.org/fcla/dt/13282
Subject Headings
Cell differentiation, Drosophila--Cytology, Molecular genetics, Reproduction--Physiological aspects, Glycoproteins
Format
Document (PDF)
Cells and cocktails
Title
Cells and cocktails: antioxidants rescue carcinogen induced mitotic defects in both chromosomally stable and unstable cells.
Creator
Griffin, Isabel Sloan., Harriet L. Wilkes Honors College
Abstract/Description
Tumor cells are characterized by an increase in genomic instability, brought about by both chromosomal rearrangement and chromosomal instability. Both of these broad changes can be induced by exposure to carcinogens. During mitosis, cells can exhibit early and late lagging chromosomes, multipolar spindles or anaphase bridges, all of which contribute to genomic rearrantement. We have studied the link between exposure to carcinogen and prevalence of mitotic defect in both chromosomally stable...
Show moreTumor cells are characterized by an increase in genomic instability, brought about by both chromosomal rearrangement and chromosomal instability. Both of these broad changes can be induced by exposure to carcinogens. During mitosis, cells can exhibit early and late lagging chromosomes, multipolar spindles or anaphase bridges, all of which contribute to genomic rearrantement. We have studied the link between exposure to carcinogen and prevalence of mitotic defect in both chromosomally stable and unstable cell lines as well as ecamined the restorative effects of antioxidants in preventing mitotic defects. We have exposed MES-SA uterine cancer cells to vinyl chloride followed by exposure to an antioxidant : ascorbic acid, B-carotene, or lycopene. Treated cells were then scored for the prevalence of mitotic defects within the population and compared to controls. We have also investigated whether pre-treatment with the antioxidants will weaken the effects of carcinogen exposure in these cell lines.
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Date Issued
2012
PURL
http://purl.flvc.org/FAU/3359304
Subject Headings
Cellular signal transduction, Cell differentiation, Medical genetics, Cancer, Genetic aspects, Antioxidants, Therapeutic use, Cancer, Chemoprevention, Apoptosis, Molecular aspects, Genetic regulation
Format
Document (PDF)
Cell-surface glycan-lectin interactions for biomedical applications
Title
Cell-surface glycan-lectin interactions for biomedical applications.
Creator
Rodriguez Benavente, Maria Carolina, Lepore, Salvatore D., Cudic, Predrag, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
Carbohydrate recognition is one of the most sophisticated recognition processes in biological systems, mediating many important aspects of cell-cell recognition, such as inflammation, cell differentiation, and metastasis. Consequently, lectin-glycan interactions have been intensively studied in order to mimic their actions for potential bioanalytical and biomedical applications. Galectins, a class of ß-galactoside-specific animal lectins, have been strongly implicated in inflammation and...
Show moreCarbohydrate recognition is one of the most sophisticated recognition processes in biological systems, mediating many important aspects of cell-cell recognition, such as inflammation, cell differentiation, and metastasis. Consequently, lectin-glycan interactions have been intensively studied in order to mimic their actions for potential bioanalytical and biomedical applications. Galectins, a class of ß-galactoside-specific animal lectins, have been strongly implicated in inflammation and cancer. Galectin-3 is involved in carbohydrate-mediated metastatic cell heterotypic and homotypic adhesion via interaction with Thomsen-Friedenreich (TF) antigen on cancer-associated MUC1. However, the precise mechanism by which galectin-3 recognizes TF antigen is poorly understood. Our thermodynamic studies have shown that the presentation of the carbohydrate ligand by MUC1-based peptide scaffolds can have a major impact on recognition, and may facilitate the design of more potent and specific galectin-3 inhibitors that can be used as novel chemical tools in dissecting the precise role of galectin-3 in cancer and inflammatory diseases. Another lectin, odorranalectin (OL), has been recently identified from Odorrana grahami skin secretions as the smallest cyclic peptide lectin, has a particular selectivity for L-fucose and very low toxicity and immunogenicity, rendering OL an excellent candidate for drug delivery to targeted sites, such as: (1) tumor-associated fucosylated antigens implicated in the pathogenesis of several cancers, for overcoming the nonspecificity of most anticancer agents; (2) the olfactory epithelium of nasal mucosa for enhanced delivery of peptide-based drugs to the brain.
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Date Issued
2015
PURL
http://purl.flvc.org/fau/fd/FA00004405
Subject Headings
Biopharmaceutics, Carbohydrates -- Therapeutic use, Cell differentiation, Drug delivery systems, Glycoproteins, Glycoslation, Mice as laboratory animals, Peptides -- Derivatives, Pharmaceutical biotechnology
Format
Document (PDF)
Investigating the Role of CHI3L1 in Promoting Tumor Growth and Metastasis Using Mammary Tumor Models
Title
Investigating the Role of CHI3L1 in Promoting Tumor Growth and Metastasis Using Mammary Tumor Models.
Creator
Libreros, Stephania, Iragavarapu-Charyulu, Vijaya, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
Metastasis is the primary cause of mortality in women with breast cancer. Recently, elevated serum levels of a glycoprotein known as chitinase-3 likeprotein- 1 (CHI3L1) has been correlated with poor prognosis and shorter survival of patients with cancer and inflammatory diseases. The biological and physiological functions of CHI3L1 in tumor progression have not yet been elucidated. In this document, we describe the role of CHI3L1 in tumor growth and metastasis and its relationship with...
Show moreMetastasis is the primary cause of mortality in women with breast cancer. Recently, elevated serum levels of a glycoprotein known as chitinase-3 likeprotein- 1 (CHI3L1) has been correlated with poor prognosis and shorter survival of patients with cancer and inflammatory diseases. The biological and physiological functions of CHI3L1 in tumor progression have not yet been elucidated. In this document, we describe the role of CHI3L1 in tumor growth and metastasis and its relationship with inflammation. Using well-established models of breast cancer, we show that CHI3L1 is increased in the serum of tumor bearing mice. We found that CHI3L1 levels are increased at both the “pre-metastatic” and “metastatic stage” and that tumor cells, splenic, alveolar and interstitial macrophages; and myeloid derived population produce CHI3L1. Furthermore, we demonstrated that CHI3L1 has an inhibitory role on the expression of interferon-gamma (IFN γ) by T cells, while enhancing the production of pro-inflammatory mediators by macrophages such as Cchemokine ligand 2 (CCL2/MCP-1), Chemokine CX motif ligand 2 (CXCL2/IL-8) and matrix metalloproteinase-9 (MMP-9), all of which promote tumor growth and metastasis. We demonstrated that in vivo treatment of tumor-bearing mice with chitin microparticles, a TH1 adjuvant and a substrate for CHI3L1, promoted immune effector functions with increased production of IFN-γ but decreased CCL2/MCP-1, CXCL2/IL-8 and MMP-9 expression by splenic and pulmonary macrophages. Significantly, in vivo administration of chitin microparticles decreased tumor growth and pulmonary metastasis in mammary tumor bearing mice. These results suggest that CHI3L1 may play a role in tumor progression. Inflammation plays a pivotal role during tumor progression and metastasis by promoting the production of pro-inflammatory molecules such as CHI3L1. However, little is known about how CHI3L1 expression can affect secondary sites to enhance metastasis. In these studies, we demonstrated that CHI3L1 alters the cellular composition and inflammatory mediators that aid in the establishment of a metastatic niche for the support of infiltrating tumor cells leading to accelerated tumor progression. Since previous studies showed that CHI3L1 modulates inflammation, we determined the role of CHI3L1 in the context of pre-existing inflammation and metastasis. We found that CHI3L1 deficient mice with preexisting inflammation had decreased pro-inflammatory mediators, and significant reduction in tumor volume and metastasis compared to wild type controls. Preexisting inflammation and CHI3L1 may be driving the establishment of a premetastatic milieu in the lungs and aiding in the establishment of metastasis. Understanding the role of CHI3L1 in inflammation during tumor progression could result in the design of targeted therapies for breast cancer patients.
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Date Issued
2015
PURL
http://purl.flvc.org/fau/fd/FA00004517, http://purl.flvc.org/fau/fd/FA00004517
Subject Headings
Biopharmaceutics, Breast -- Cancer -- Etiology, Breast -- Cancer -- Molecular aspects, Cell differentiation, Chitinase, Glycoproteins -- Metabolism, Inflammation, Mice as laboratory animals
Format
Document (PDF)
Highwire's characterization and signaling roles in Drosophila central synapse formation
Title
Highwire's characterization and signaling roles in Drosophila central synapse formation.
Creator
Rowland, Kimberly Diane., Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
The assembly and maintenance of central synapses is a complex process, requiring myriad genes and their products. Highwire is a large gene containing a RING domain, characteristic of ubiquitin E3 ligases. Highwire has been shown to restrain axon growth and control synaptogenesis at a peripheral synapse. Here I examine the roles of Highwire at a central synapse in the adult Drosophila Giant Fiber System (GFS). Highwire is indeed necessary for proper axonal growth as well as synaptic...
Show moreThe assembly and maintenance of central synapses is a complex process, requiring myriad genes and their products. Highwire is a large gene containing a RING domain, characteristic of ubiquitin E3 ligases. Highwire has been shown to restrain axon growth and control synaptogenesis at a peripheral synapse. Here I examine the roles of Highwire at a central synapse in the adult Drosophila Giant Fiber System (GFS). Highwire is indeed necessary for proper axonal growth as well as synaptic transmission in the GFS. Differences arise between the central synapse and the neuromuscular junction (NMJ), where highwire was initially characterized : expresion from the postsynaptic cell can rescue highwire synaptic defects, which is not seen at the NMJ. In addition, a MAP kinase signaling pathway regulated by highwire at the NMJ has differing roles at a central synapse. Wallenda MAPK can rescue not only the highwire anatomical phenotype but also the defects seen in transmission. Another distinction is seen here : loss of function basket and Dfos enhance the highwire anatomical phenotype while expression of dominant negative basket and Dfos suppress the highwire phenotype. As a result we have compared the signaling pathway in flies and worms and found that the NMJ in the two organisms use a parallel pathway while the central synapse uses a distinct pathway.
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Date Issued
2012
PURL
http://purl.flvc.org/FAU/3352826
Subject Headings
Cellular control mechanisms, Cellular signal transduction, Cell differentiation, Gene expression, Genetic transcription, Transcription factors, Drosophila melanogaster, Cytogenetics
Format
Document (PDF)
Developmental and Protective Mechanisms of the Ocular Lens.
Title
Developmental and Protective Mechanisms of the Ocular Lens.
Creator
Chauss, Daniel C., Kantorow, Marc, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biomedical Science
Abstract/Description
The vertebrate eye lens functions to focus light onto the retina to produce vision. The lens is composed of an anterior monolayer of cuboidal epithelial cells that overlie a core of organelle free fiber cells. The lens develops and grows throughout life by the successive layering of lens fiber cells via their differentiation from lens epithelial cells. Lens developmental defect and damage to the lens are associated with cataract formation, an opacity of the lens that is a leading cause of...
Show moreThe vertebrate eye lens functions to focus light onto the retina to produce vision. The lens is composed of an anterior monolayer of cuboidal epithelial cells that overlie a core of organelle free fiber cells. The lens develops and grows throughout life by the successive layering of lens fiber cells via their differentiation from lens epithelial cells. Lens developmental defect and damage to the lens are associated with cataract formation, an opacity of the lens that is a leading cause of visual impairment worldwide. The only treatment to date for cataract is by surgery. Elucidating those molecules and mechanisms that regulate the development and lifelong protection of the lens is critical toward the development of future therapies to prevent or treat cataract. To determine those molecules and mechanisms that may be important for these lens requirements we employed high-throughput RNA sequencing of microdissected differentiation statespecific lens cells to identify an extensive range of transcripts encoding proteins expressed by these functionally distinct cell types. Using this data, we identified differentiation state-specific molecules that regulate mitochondrial populations between lens epithelial cells that require the maintenance of a functional population of mitochondria and lens fiber cells that must eliminate their mitochondria for their maturation. In addition, we discovered a novel mechanism for how lens epithelial cells clear apoptotic cell debris that could arise from damage to the lens and found that UVlight likely compromises this system. Moreover, the data herein provide a framework to determine novel lens cell differentiation state-specific mechanisms. Future studies are required to determine the requirements of the identified molecules and mechanisms during lens development, lens defense against damage, and cataract formation.
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Date Issued
2016
PURL
http://purl.flvc.org/fau/fd/FA00004577
Subject Headings
Eye--Diseases--Etiology., Cell differentiation., Cellular signal transduction., Protein folding., Mitochondrial pathology., Cellular control mechanisms., Apoptosis., Oxidative stress--Prevention.
Format
Document (PDF)