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- Title
- Analysis of the Role of Autophagy in Dauer Formation and Dauer Recovery Regulated by TGF-β Signaling Pathway in Caenorhabditis elegans.
- Creator
- Ritter, Portia, Jia, Kailiang, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
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Caenorhabditis elegans optionally enter into a dauer diapause phase that results in a prolonged life in a semi-dormant state. Entry into and recovery from dauer diapause includes many physical changes in body structure, physiology, and gene expression. Entry into dauer diapause is regulated by several signaling pathways including transforming growth factor (TGF-β). Autophagy plays an important role in dauer formation and recover. During dauer transformation autophagy is up-regulated and may...
Show moreCaenorhabditis elegans optionally enter into a dauer diapause phase that results in a prolonged life in a semi-dormant state. Entry into and recovery from dauer diapause includes many physical changes in body structure, physiology, and gene expression. Entry into dauer diapause is regulated by several signaling pathways including transforming growth factor (TGF-β). Autophagy plays an important role in dauer formation and recover. During dauer transformation autophagy is up-regulated and may play a role in remodeling the molecular structure for long term survival during dauer diapause. This research helps determine the role of autophagy in dauer development and recovery mediated through the TGF-β signaling pathway. This research also determines in which tissue autophagy is necessary for dauer formation and recovery through TGF-β signaling. This research is shedding light on the function of autophagy in the TGF-β signaling pathway, both processes of which have been linked to tumorigenesis, heart disease and cancer.
Show less - Date Issued
- 2017
- PURL
- http://purl.flvc.org/fau/fd/FA00004921, http://purl.flvc.org/fau/fd/FA00004921
- Subject Headings
- Aging--Molecular aspects., Aging--Physiological aspects., Caenorhabditis elegans--Molecular genetics., Autophagic vacuoles., Gene expression., Apoptosis., Cellular signal transduction., DNA-binding proteins., Transforming growth factors-beta--Receptors.
- Format
- Document (PDF)
- Title
- Characterization of receptor protein tyrosine phosphatase PTP69D in the giant fiber circuit.
- Creator
- Lee, LaTasha Hoskins, Godenschwege, Tanja A., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
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PTP69D is a receptor protein tyrosine phosphatase (RPTP) with two intracellular catalytic domains (Cat1 and Cat2), which has been shown to play a role in axon outgrowth and guidance of embryonic motorneurons, as well as targeting of photoreceptor neurons in the visual system of Drosophila melanogaster. Here, we characterized the developmental role of PTP69D in the giant fiber (GF) neurons; two interneurons in the central nervous system (CNS) that control the escape response of the fly. In...
Show morePTP69D is a receptor protein tyrosine phosphatase (RPTP) with two intracellular catalytic domains (Cat1 and Cat2), which has been shown to play a role in axon outgrowth and guidance of embryonic motorneurons, as well as targeting of photoreceptor neurons in the visual system of Drosophila melanogaster. Here, we characterized the developmental role of PTP69D in the giant fiber (GF) neurons; two interneurons in the central nervous system (CNS) that control the escape response of the fly. In addition to guidance and targeting functions, our studies reveal an additional role for PTP69D in synaptic terminal growth in the CNS. We found that inhibition of phosphatase activity in catalytic domain (Cat1) proximal to the transmembrane domain did not affect axon guidance or targeting but resulted in stunted terminal growth of the GFs. Cell autonomous rescue and knockdown experiments demonstrated a function for PTP69D in the GFs, but not its postsynaptic target neurons. In addition,complementation studies and structure-function analyses revealed that for GF terminal growth, Cat1 function of PTP69D requires the immunoglobulin and the Cat2 domain but not the fibronectin type III repeats nor the membrane proximal region. In contrast, the fibronectin type III repeats, but not the immunoglobulin domains, were previously shown to be essential for axon targeting of photoreceptor neurons. Thus, our studies uncover a novel role for PTP69D in synaptic terminal growth in the CNS that is mechanistically distinct from its function during earlier developmental processes.
Show less - Date Issued
- 2014
- PURL
- http://purl.flvc.org/fau/fd/FA00004301, http://purl.flvc.org/fau/fd/FA00004301
- Subject Headings
- Drosophila melanogaster., Protein-tyrosine phosphatase--Metabolism., Protein-tyrosine kinase., Protein kinases--Inhibitors., Phosphoprotein phosphatases., Transcription factors., Cell receptors., Cellular signal transduction.
- Format
- Document (PDF)
- Title
- DNA fingerprints of human oral microbiome: a first step towards early diagnosis of oral diseases.
- Creator
- Chakraborty, Shreyasee, Esiobu, Nwadiuto, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
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This study evaluated the stability of oral bacteria in healthy subjects and documented community shifts in smokers and oral/periodontal disease by employing PCR-RFLP, DGGE and sequence analysis of the 16S rDNA gene from metagenomes and plate-wash (cultured) bacteria of oral wash from 15 participants,. A stable core of bacterial DNA fingerprint was detected within and between subjects and did not change over time when analyzed in smokers and healthy non-smokers. Signature bands in smokers, non...
Show moreThis study evaluated the stability of oral bacteria in healthy subjects and documented community shifts in smokers and oral/periodontal disease by employing PCR-RFLP, DGGE and sequence analysis of the 16S rDNA gene from metagenomes and plate-wash (cultured) bacteria of oral wash from 15 participants,. A stable core of bacterial DNA fingerprint was detected within and between subjects and did not change over time when analyzed in smokers and healthy non-smokers. Signature bands in smokers, non-smokers and periodontal disease subjects were evident suggesting the presence of potential indicators of health and poor oral health. Taxon diversity was higher in smokers including members of the genera Rothia, Synechococcus, Neisseria, Thiomargarita and Pyrobaculum but highest in periodontal disease. The two techniques successfully aligned the subjects within appropriate categories (based on their oral microbial genetic patterns)confirming their diagnostic suitability.
Show less - Date Issued
- 2014
- PURL
- http://purl.flvc.org/fau/fd/FA00004184, http://purl.flvc.org/fau/fd/FA00004184
- Subject Headings
- Molecular microbiology., Mouth--Microbiology., Bacterial genetics., Cellular signal transduction., Microbial genomics.
- Format
- Document (PDF)
- Title
- Molecular Mechanisms Of CaV2.1 Expression and Functional Organization at the Presynaptic Terminal.
- Creator
- Das, Brati, Young, Samuel M., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
-
Neuronal circuit output is dependent on the embedded synapses’ precise regulation of Ca2+ mediated release of neurotransmitter filled synaptic vesicles (SVs) in response to action potential (AP) depolarizations. A key determinant of SV release is the specific expression, organization, and abundance of voltage gated calcium channel (VGCC) subtypes at presynaptic active zones (AZs). In particular, the relative distance that SVs are coupled to VGCCs at AZs results in two different modes of SV...
Show moreNeuronal circuit output is dependent on the embedded synapses’ precise regulation of Ca2+ mediated release of neurotransmitter filled synaptic vesicles (SVs) in response to action potential (AP) depolarizations. A key determinant of SV release is the specific expression, organization, and abundance of voltage gated calcium channel (VGCC) subtypes at presynaptic active zones (AZs). In particular, the relative distance that SVs are coupled to VGCCs at AZs results in two different modes of SV release that dramatically impacts synapse release probability and ultimately the neuronal circuit output. They are: “Ca2+ microdomain,” SV release due to cooperative action of many loosely coupled VGCCs to SVs, or “Ca2+ nanodomain,” SV release due to fewer more tightly coupled VGCCs to SVs. VGCCs are multi-subunit complexes with the pore forming a1 subunit (Cav2.1), the critical determinant of the VGCC subtype kinetics, abundance, and organization at the AZ. Although in central synapses Cav2.2 and Cav2.1 mediate synchronous transmitter release, neurons express multiple VGCC subtypes with differential expression patterns between the cell body and the pre-synapse. The calyx of Held, a giant axosomatic glutamatergic presynaptic terminal that arises from the globular bushy cells (GBC) in the cochlear nucleus, exclusively uses Cav2.1 VGCCs to support the early stages of auditory processing. Due to its experimental accessibility the calyx provides unparalleled opportunities to gain mechanistic insights into Cav2.1 expression, organization, and SV release modes at the presynaptic terminal. Although many molecules are implicated in mediating Cav2.1 expression and SV to VGCC coupling through multiple binding domains on the C-terminus of the Cav2.1 a1 subunit, the underlying fundamental molecular mechanisms remain poorly defined. Here, using viral vector mediated approaches in combination with Cav2.1 conditional knock out transgenic mice, we demonstrate that that there a two independent pathways that control Cav2.1 expression and SV to VGCC coupling at the calyx of Held. These implications for the regulation of synaptic transmission in CNS synapses are discussed.
Show less - Date Issued
- 2016
- PURL
- http://purl.flvc.org/fau/fd/FA00004584
- Subject Headings
- Synapses., Neural transmission., Cellular signal transduction.
- Format
- Document (PDF)
- Title
- Presynaptic Determinants of Synaptic Strength and Energy Efficiency at Drosophila Neuromuscular Junctions.
- Creator
- Lu, Zhongmin, Macleod, Gregory, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
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Changes in synaptic strength underlie synaptic plasticity, the cellular substrate for learning and memory. Disruptions in the mechanisms that regulate synaptic strength closely link to many developmental, neurodegenerative and neurological disorders. Release site probability (PAZ) and active zone number (N) are two important presynaptic determinants of synaptic strength; yet, little is known about the processes that establish the balance between N and PAZ at any synapse. Furthermore, it is...
Show moreChanges in synaptic strength underlie synaptic plasticity, the cellular substrate for learning and memory. Disruptions in the mechanisms that regulate synaptic strength closely link to many developmental, neurodegenerative and neurological disorders. Release site probability (PAZ) and active zone number (N) are two important presynaptic determinants of synaptic strength; yet, little is known about the processes that establish the balance between N and PAZ at any synapse. Furthermore, it is not known how PAZ and N are rebalanced during synaptic homeostasis to accomplish circuit stability. To address this knowledge gap, we adapted a neurophysiological experimental system consisting of two functionally differentiated glutamatergic motor neurons (MNs) innervating the same target. Average PAZ varied between nerve terminals, motivating us to explore benefits for high and low PAZ, respectively. We speculated that high PAZ confers high-energy efficiency. To test the hypothesis, electrophysiological and ultrastructural measurements were made. The terminal with the highest PAZ released more neurotransmitter but it did so with the least total energetic cost. An analytical model was built to further explore functional and structural aspects in optimizing energy efficiency. The model supported that energy efficiency optimization requires high PAZ. However, terminals with low PAZ were better able to sustain neurotransmitter release. We suggest that tension between energy efficiency and stamina sets PAZ and thus determines synaptic strength. To test the hypothesis that nerve terminals regulate PAZ rather than N to maintain synaptic strength, we induced sustained synaptic homeostasis at the nerve terminals. Ca2+ imaging revealed that terminals of the MN innervating only one muscle fiber utilized greater Ca2+ influx to achieve compensatory neurotransmitter release. In contrast, morphological measurements revealed that terminals of the MN inner vating multiple postsynaptic targets utilized an increase in N to achieve compensatory neurotransmitter release, but this only occurred at the terminal of the affected postsynaptic target. In conclusion, this dissertation provides several novel insights into a prominent question in neuroscience: how is synaptic strength established and maintained. The work indicates that tension exists between energy efficiency and stamina in neurotransmitter release likely influences PAZ. Furthermore, PAZ and N are rebalanced differently between terminals during synaptic homeostasis.
Show less - Date Issued
- 2015
- PURL
- http://purl.flvc.org/fau/fd/FA00004519, http://purl.flvc.org/fau/fd/FA00004519
- Subject Headings
- Drosophila melanogaster--Nervous system., Drosophila melanogaster--Cytogenetics., Fruit-flies--Development., Fruit-flies--Nervous system., Genetic transcription., Transcription factors., Cellular signal transduction., Cellular control mechanisms., Myoneural junction.
- Format
- Document (PDF)
- Title
- Reduced Reproductivity and Larval Locomotion in the Absence of Methionine Sulfoxide Reductase in Drosophila.
- Creator
- Singkornrat, Diana, Binninger, David, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
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The inevitable aging process can be partially attributed to the accumulation of oxidative damage that results from the action of free radicals. Methionine sulfoxide reductases (Msr) are a class of enzymes that repair oxidized methionine residues. The two known forms of Msr are MsrA and MsrB which reduce the R- and S- enantiomers of methionine sulfoxide, respectively. Our lab has created the first genetic animal model that is fully deficient for any Msr activity. Previously our lab showed that...
Show moreThe inevitable aging process can be partially attributed to the accumulation of oxidative damage that results from the action of free radicals. Methionine sulfoxide reductases (Msr) are a class of enzymes that repair oxidized methionine residues. The two known forms of Msr are MsrA and MsrB which reduce the R- and S- enantiomers of methionine sulfoxide, respectively. Our lab has created the first genetic animal model that is fully deficient for any Msr activity. Previously our lab showed that these animals exhibit a 20 hour delay in development of the third instar larvae (unpublished data). My studies have further shown that the prolonged third-instar stage is due to a reduced growth rate associated with slower food intake and a markedly slower motility. These Msr-deficient animals also exhibit decreased egg-laying that can be attributed to a lack of female receptivity to mating.
Show less - Date Issued
- 2016
- PURL
- http://purl.flvc.org/fau/fd/FA00004777, http://purl.flvc.org/fau/fd/FA00004777
- Subject Headings
- Proteins--Chemical modification., Oxidative stress., Oxidation-reduction reaction., Drosophila melanogaster--Genetics., Mitochondrial pathology., Cellular signal transduction., Mutation (Biology), Aging--Molecular aspects.
- Format
- Document (PDF)
- Title
- Synaptic Rearrangements and the Role of Netrin-Frazzled Signaling in Shaping the Drosophila Giant Fiber Circuit.
- Creator
- Lloyd, Brandon N., Murphey, Rodney K., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
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In the developing CNS, presynaptic neurons often have exuberant overgrowth and form excess (and overlapping) postsynaptic connections. Importantly, these excess connections are refined during circuit maturation so that only the appropriate connections remain. This synaptic rearrangement phenomenon has been studied extensively in vertebrates but many of those models involve complex neuronal circuits with multiple presynaptic inputs and postsynaptic outputs. Using a simple escape circuit in...
Show moreIn the developing CNS, presynaptic neurons often have exuberant overgrowth and form excess (and overlapping) postsynaptic connections. Importantly, these excess connections are refined during circuit maturation so that only the appropriate connections remain. This synaptic rearrangement phenomenon has been studied extensively in vertebrates but many of those models involve complex neuronal circuits with multiple presynaptic inputs and postsynaptic outputs. Using a simple escape circuit in Drosophila melanogaster (the giant fiber circuit), we developed tools that enabled us to study the molecular development of this circuit; which consists of a bilaterally symmetrical pair of presynaptic interneurons and postsynaptic motorneurons. In the adult circuit, each presynaptic interneuron (giant fiber) forms a single connection with the ipsilateral, postsynaptic motorneuron (TTMn). Using new tools that we developed we labeled both giant fibers throughout their development and saw that these neurons overgrew their targets and formed overlapping connections. As the circuit matured, giant fibers pruned their terminals and refined their connectivity such that only a single postsynaptic connection remained with the ipsilateral target. Furthermore, if we ablated one of the two giant fibers during development in wildtype animals, the remaining giant fiber often retained excess connections with the contralateral target that persisted into adulthood. After demonstrating that the giant fiber circuit was suitable to study synaptic rearrangement, we investigated two proteins that might mediate this process. First, we were able to prevent giant fibers from refining their connectivity by knocking out highwire, a ubiquitin ligase that prevented pruning. Second, we investigated whether overexpressing Netrin (or Frazzled), part of a canonical axon guidance system, would affect the refinement of giant fiber connectivity. We found that overexpressing Netrin (or Frazzled) pre- & postsynaptically resulted in some giant fibers forming or retaining excess connections, while exclusively presynaptic (or postsynaptic) expression of either protein had no effect. We further showed that by simultaneously reducing (Slit-Robo) midline repulsion and elevating Netrin (or Frazzled) pre- & postsynaptically, we significantly enhanced the proportion of giant fibers that formed excess connections. Our findings suggest that Netrin-Frazzled and Slit-Robo signaling play a significant role in refining synaptic circuits and shaping giant fiber circuit connectivity.
Show less - Date Issued
- 2016
- PURL
- http://purl.flvc.org/fau/fd/FA00004758, http://purl.flvc.org/fau/fd/FA00004758
- Subject Headings
- Drosophila melanogaster--Cytogenetics., Genetic transcription., Transcription factors., Cellular signal transduction., Cellular control mechanisms., Cell receptors.
- Format
- Document (PDF)
- Title
- The Impact of Pharmacological Targeting of Abnormal Tumor Metabolism with 3-Bromopyruvate on Dendritic Cell Mediated Tumoral Immunity.
- Creator
- Lang, Kevin, Hartmann, James X., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
- Abstract/Description
-
Studies have shown that tumor cells are susceptible to pharmacological targeting of their altered glycolytic metabolism with a variety of compounds that result in apoptosis. One such compound, 3-bromopyruvate (3-BP), has been shown to eradicate cancer in an animal model. However, no studies have shown whether the apoptotic fragments resulting from 3-BP treatment have the capacity to elicit an immunogenic cell death that activates dendritic cells, the primary antigen presenting cell in the...
Show moreStudies have shown that tumor cells are susceptible to pharmacological targeting of their altered glycolytic metabolism with a variety of compounds that result in apoptosis. One such compound, 3-bromopyruvate (3-BP), has been shown to eradicate cancer in an animal model. However, no studies have shown whether the apoptotic fragments resulting from 3-BP treatment have the capacity to elicit an immunogenic cell death that activates dendritic cells, the primary antigen presenting cell in the immune system. Immunogenic cell death is critical to eliciting an effective adaptive immune response that selectively kills additional target cells and generates immunological memory. We demonstrated that 3-bromopyruvate induced apoptosis in a number of different murine breast cancer cell lines, including the highly metastatic 4T1 line. The dying tumor cells stimulated immature dendritic cells (DCs) of the immortal JAWS II cell line to produce high levels of the pro-inflammatory cytokine IL-12, and increased their expression of key co-stimulatory molecules CD80 and CD86. The activated dendritic cells showed increased uptake of fragments from dying tumor cells that correlated with the increased levels of calreticulin on the surface and release of high group motility box 1 (HMGB1) of the latter following 3-BP treatment. Additionally, the anti-phagocytic signal CD47 present on breast cancer cells was reduced by treatment with 3-bromopyruvate when compared to the levels on untreated 4T1 cells. 3-BP treated breast cancer cells were able to activate dendritic cells through TLR4 signaling. Signaling was dependent on both the expression of surface calreticulin and on the extracellular release of high mobility group box 1 protein (HMGB1) during the process of immunogenic cell death. Killing by 3-BP was compared to mitoxantrone and doxorubicin, among the few chemotherapeutics that induce immunogenic cell death. 3-BP killing was likewise compared to camptothecin, a compound that fails to induce immunogenic cell death. Importantly, 3-BP did not markedly decrease the levels of the key peptide presenting molecule MHC I on DCs that were co-cultivated with dying tumor cells. Treatment of the highly aggressive triple negative BT-20 human breast cancer cell line with 3-BP also induced an immunogenic cell death, activating human dendritic cells in vitro.
Show less - Date Issued
- 2017
- PURL
- http://purl.flvc.org/fau/fd/FA00004834
- Subject Headings
- Apoptosis., Cellular signal transduction., Cell death., Breast--Cancer--Treatment., Carrier proteins., Cancer--Molecular aspects., Biological interfaces.
- Format
- Document (PDF)
