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Title: In Vivo Characterization of a Novel GLP-1R Biased Agonist.
Creator: Turn, Rachel, McDonald, Patricia, Kirchman, Paul, Harriet L. Wilkes Honors College
Abstract/Description: In the twenty-first century one of the most widespread and challenging human disorders is Type 2 Diabetes Mellitus (T2DM). Standard therapies are effective in achieving glycemic control but have undesired side effects, such as hypoglycemia and weight gain. As a result, there is an urgent need to develop novel therapeutics to treat this devastating disease. The Glucagon-like peptide receptor (GLP-1R) plays a critical role in glucose homeostasis and is therefore an attractive target for...
Show moreIn the twenty-first century one of the most widespread and challenging human disorders is Type 2 Diabetes Mellitus (T2DM). Standard therapies are effective in achieving glycemic control but have undesired side effects, such as hypoglycemia and weight gain. As a result, there is an urgent need to develop novel therapeutics to treat this devastating disease. The Glucagon-like peptide receptor (GLP-1R) plays a critical role in glucose homeostasis and is therefore an attractive target for treatment of T2DM. GLP-1R exhibits pleiotropic signaling, so to determine if activation of one signaling pathway to the exclusion of others will provide improved therapeutics, we sought to identify GLP-1R biased ligands. Screening of large lentivirus-encoded combinatorial peptide libraries identified a novel GLP-1R ligand (peptide SR) exhibiting functional selectivity. Here, we describe the in vitro and in vivo pharmacological characterization of peptide SR and highlight the differences observed between this treatment and the reference ligand, Exendin-4.
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Date Issued: 2015
PURL: http://purl.flvc.org/fau/fd/FA00003660
Format: Document (PDF)

Title: The maturation of GABAergic circuitry in ferret visual cortex.
Creator: Casciato, Dominick Joseph, Jacob, Amanda, Kirchman, Paul, Harriet L. Wilkes Honors College
Abstract/Description: Experience plays a critical role in maturation of cortical circuits. In visual cortex, experience-dependent development has been linked to the maturation of inhibitory interneurons. Parvalbumin-containing (PV) interneurons, a subtype of GABAergic interneurons, play an important role in cortical circuit function; however, it remains unknown how visual experience shapes their organization. We used immunohistochemistry to observe the organization of PV expression in visual cortex through visual...
Show moreExperience plays a critical role in maturation of cortical circuits. In visual cortex, experience-dependent development has been linked to the maturation of inhibitory interneurons. Parvalbumin-containing (PV) interneurons, a subtype of GABAergic interneurons, play an important role in cortical circuit function; however, it remains unknown how visual experience shapes their organization. We used immunohistochemistry to observe the organization of PV expression in visual cortex through visual maturity. Before visual experience, PV cell bodies and processes are most pronounced in layer 5, less in layer 2/3, and generally lacking in layer 4. Within 3 days of the onset of visual experience, PV organization undergoes a major shift, with PV expression found throughout layers 2-6. We performed dark rearing which determined that these morphological changes are due to visual experience. This rapid change in parvalbumin organization may play a role in functional changes associated with the onset of visual experience.
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Date Issued: 2015
PURL: http://purl.flvc.org/fau/fd/FA00003639
Format: Document (PDF)

Title: Artificial evolution of aconitase via heat-shock induced oxidative stress.
Creator: Crary, Sean, Kirchman, Paul, Harriet L. Wilkes Honors College
Abstract/Description: Oxidative stress, where oxygen has an unpaired electron, has been shown to damage cellular components. These electrons injure local cellular machinery and have the potential to interrupt major protein pathways. Aconitase is a key polypeptide with multiple niches in the cell, and has been shown to be a target for free radical impairment. We utilize artificial evolution using heat shock to cause major oxidative damage. With up to 99% fatality and repeated exposure we have an effective way to...
Show moreOxidative stress, where oxygen has an unpaired electron, has been shown to damage cellular components. These electrons injure local cellular machinery and have the potential to interrupt major protein pathways. Aconitase is a key polypeptide with multiple niches in the cell, and has been shown to be a target for free radical impairment. We utilize artificial evolution using heat shock to cause major oxidative damage. With up to 99% fatality and repeated exposure we have an effective way to select against aconitase mutants via respiratory deficient yeast on glycerol, a non-fermentable growth medium. In this experiment, we use the previously described artificial evolution coupled with error-prone PCR to select for heat-resistant aconitase mutants. The results are in the form of purified DNA from different clones. These will give future insight on the important enzymatic domains of aconitase.
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Date Issued: 2015
PURL: http://purl.flvc.org/fau/fd/FA00003641
Format: Document (PDF)

Title: Cortical Development in an Intellectual Disability (ID) Mouse Model.
Creator: Shotwell, Kaitlyn, Kirchman, Paul, Harriet L. Wilkes Honors College
Abstract/Description: Intellectual disability (ID) is a neurodevelopmental disorder characterized by significant limitations in both adaptive behavior and intellectual function that arises prior to reaching adulthood. Studies revealed a prevailing correlation between patients with ID and a sporadic SYNGAP-1 gene mutation. The SYNGAP-1 gene encodes for the protein SYNGAP that controls intracellular signaling and is directly linked with synaptic transmission. Mouse models were used to analyze the structure of...
Show moreIntellectual disability (ID) is a neurodevelopmental disorder characterized by significant limitations in both adaptive behavior and intellectual function that arises prior to reaching adulthood. Studies revealed a prevailing correlation between patients with ID and a sporadic SYNGAP-1 gene mutation. The SYNGAP-1 gene encodes for the protein SYNGAP that controls intracellular signaling and is directly linked with synaptic transmission. Mouse models were used to analyze the structure of somatosensory cortical neurons in different layers of the cortex during brain development. Neurons of SynGAP-1 mutant mice in layer V of the somatosensory cortex displayed a much more complex structure than the wildtype during development but no differences once they reached adulthood. Adversely, in layer II/III, the neurons of mutant mice were less complex during the developmental stages. This research suggests that a SynGAP-1 haploinsufficiency causes ID by disrupting the natural timing of neuronal growth and brain development.
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Date Issued: 2015
PURL: http://purl.flvc.org/fau/fd/FA00003655
Format: Document (PDF)

Title: UNC-33 and RPM-1 Function in Parallel to Regulate Axon Termination.
Creator: Birnbaum, Rayna, Kirchman, Paul, Harriet L. Wilkes Honors College
Abstract/Description: Precise axon termination is necessary for the development of a functioning neuronal network within the nervous system. However, little is known about the mechanisms that regulate axon termination. C. elegans RPM-1, a conserved member of the PHR proteins, has been previously shown to regulate axon termination and synapse formation. Recently, it was shown that, when phosphorylated by Cdk5, CRMP-2 (the mammalian homolog of C. elegans UNC-33) acts as a microtubule destabilizer during axon...
Show morePrecise axon termination is necessary for the development of a functioning neuronal network within the nervous system. However, little is known about the mechanisms that regulate axon termination. C. elegans RPM-1, a conserved member of the PHR proteins, has been previously shown to regulate axon termination and synapse formation. Recently, it was shown that, when phosphorylated by Cdk5, CRMP-2 (the mammalian homolog of C. elegans UNC-33) acts as a microtubule destabilizer during axon outgrowth. We investigated the relationship between the RPM-1 and UNC-33 pathways in axon termination. Our data has lead to the conclusion that the CDK-5, UNC-33 pathway works in parallel with the RPM-1 pathway to regulate axon termination.
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Date Issued: 2016
PURL: http://purl.flvc.org/fau/fd/FA00003665
Format: Document (PDF)

Title: Discovery and Analysis of Novel Non-Electrophilic Agonists of the Nrf2-Mediated Antioxidant Response Pathway.
Creator: Rohr, Michael W., Kirchman, Paul, Harriet L. Wilkes Honors College
Abstract/Description: Cellular oxidative stress occurs when oxidant formation rate exceeds neutralization rate, shifting intracellular redox homeostasis and leading to cytotoxicity. Oxidants stimulate the Antioxidant Response Pathway (ARP) which activates Nrf2 transcription factor, increasing expression of antioxidant genes. Oxidative stress is implicated in many diseases and thus chemically targeting the ARP represents high therapeutic potential. Ironically, however, current drugs intended to simulate the ARP are...
Show moreCellular oxidative stress occurs when oxidant formation rate exceeds neutralization rate, shifting intracellular redox homeostasis and leading to cytotoxicity. Oxidants stimulate the Antioxidant Response Pathway (ARP) which activates Nrf2 transcription factor, increasing expression of antioxidant genes. Oxidative stress is implicated in many diseases and thus chemically targeting the ARP represents high therapeutic potential. Ironically, however, current drugs intended to simulate the ARP are electrophilic and function by inducing oxidative stress, thereby activating Nrf2. Therefore, non-oxidative alternatives for these drugs will increase therapeutic index, safety, and effectiveness especially in treating Rheumatoid Arthritis or Multiple Sclerosis. An initial chemical library screen of 403,862 compounds for non-electrophilic properties led to 28 hits and subsequent cell viability and ARP induction assays further decreased this number to five. Structure Activity Relationship (SAR) analysis revealed a single compound series that demonstrated preferential characteristics on all fronts tested in vitro. Further in vivo studies are needed to verify translational therapeutic properties.
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Date Issued: 2016
PURL: http://purl.flvc.org/fau/fd/FA00003689
Format: Document (PDF)

Title: RESPONSES OF A CALCIUM CHANNEL MODELTO VARIATIONS IN VOLTAGE WAVEFORM.
Creator: Tranquil, Elizabeth, Christie, Jason, Kirchman, Paul, Kundalkar, Shree, Harriet L. Wilkes Honors College
Abstract/Description: Action potential repolarization in certain neurons slows at neurotransmitter release sites in the axon if an action potential is preceded by sufficient depolarization. We hypothesize that slower repolarization allows axons to change strength of neurotransmission by changing calcium channel open probability. This was explored with a Markov model comprised of multiple calcium channel subtypes and an action potential waveform input. The model was solved for channel open probability, channel...
Show moreAction potential repolarization in certain neurons slows at neurotransmitter release sites in the axon if an action potential is preceded by sufficient depolarization. We hypothesize that slower repolarization allows axons to change strength of neurotransmission by changing calcium channel open probability. This was explored with a Markov model comprised of multiple calcium channel subtypes and an action potential waveform input. The model was solved for channel open probability, channel ionic current and charge from ionic current. The outputted charge from the model was compared to experimental calcium imaging results in neurons from mouse cerebellum. The results show that more calcium flows into the cell when the action potential is widened. This implies that in some neurons, a wider action potential may lead to opening of calcium channels that respond selectively to the duration of the action potential waveform at sites of release.
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Date Issued: 2014
PURL: http://purl.flvc.org/fau/fd/FA00003630
Format: Document (PDF)

Title: Confirmation of the existance of KAR, HAD, EAR, and PP, in the lipid metabolisms of Chlamydomonas Reinhardtii and Volvox Carteri F. Nagariensis.
Creator: Airapetov, Robert, Kirchman, Paul, Harriet L. Wilkes Honors College
Abstract/Description: The current search for an efficient form of alternative energy has put a large focus on algal biofuels. This biofuel is very efficient, environmentally friendly, and acts as a virtually inexhaustible resource. The major issue with algal biofuel is its vast consumption of space to store the large amounts of algae necessary for fuel production. This is why scientists are trying to figure out ways to make algal storage units, photobioreactors, and the algae itself more efficient. In order to do...
Show moreThe current search for an efficient form of alternative energy has put a large focus on algal biofuels. This biofuel is very efficient, environmentally friendly, and acts as a virtually inexhaustible resource. The major issue with algal biofuel is its vast consumption of space to store the large amounts of algae necessary for fuel production. This is why scientists are trying to figure out ways to make algal storage units, photobioreactors, and the algae itself more efficient. In order to do so, the lipid metabolism of algae needs to be mapped. Using pre-existing maps of algal lipid metabolism, the lipid pathways of Chlamydomonas reinhardtii and its close relation Volvox carteri f. nagariensis were inspected. The key proteins KAR, HAD, EAR, and PP, had not yet been confirmed. Therefore, using preexisting metabolism maps, BLAST, and predicted protein sequences, the existence of these proteins in the aforementioned algae has been theoretically confirmed.
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Date Issued: 2013
PURL: http://purl.flvc.org/fau/fd/FA00003501
Format: Document (PDF)

Title: Some like it hot: the isolation of an aconitase mutant resistant to heat shock-induced oxidative stress.
Creator: Enogieru, Imarhia, Kirchman, Paul, Harriet L. Wilkes Honors College
Abstract/Description: Aconitase is a multifunctional enzyme essential for mitochondrial DNA maintenance and cellular respiration. For my thesis, I used an error prone PCR mutagenesis method to mutate the yeast aconitase (ACO1) gene and created a mutant library of Sacchromyces cerevisiae yeast cells. The library underwent 50oC heat shocks to select for cells expressing an aconitase mutant that increased the cells’ resistance to heat shock-induced oxidative stress. Oxidative stress has been implicated as a theory of...
Show moreAconitase is a multifunctional enzyme essential for mitochondrial DNA maintenance and cellular respiration. For my thesis, I used an error prone PCR mutagenesis method to mutate the yeast aconitase (ACO1) gene and created a mutant library of Sacchromyces cerevisiae yeast cells. The library underwent 50oC heat shocks to select for cells expressing an aconitase mutant that increased the cells’ resistance to heat shock-induced oxidative stress. Oxidative stress has been implicated as a theory of cellular aging. Isolated aconitase mutants with increased oxidative stress resistance will be assayed for increased lifespan, which would support the free radical theory of aging and implicate aconitase as an important determinant of cellular aging.
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Date Issued: 2013
PURL: http://purl.flvc.org/fau/fd/FA00003511
Format: Document (PDF)

Harriet L. Wilkes Honors College (9)	+ -
Airapetov, Robert (1)	+ -
Birnbaum, Rayna (1)	+ -
Casciato, Dominick Joseph (1)	+ -
Christie, Jason (1)	+ -

Crary, Sean (1)	+ -
Enogieru, Imarhia (1)	+ -
Jacob, Amanda (1)	+ -
Kundalkar, Shree (1)	+ -
McDonald, Patricia (1)	+ -
Rohr, Michael W. (1)	+ -
Shotwell, Kaitlyn (1)	+ -
Tranquil, Elizabeth (1)	+ -
Turn, Rachel (1)	+ -

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