Browsing by Author "Baucum, A.J."

Now showing 1 - 6 of 6
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    Developmental signaling pathways in adult energy homeostasis
    (2021-08) Antonellis, Patrick; Berbari, Nicolas; Baucum, A.J.; Adams, Andrew; Perrin, Benjamin
    Many signaling pathways which are classically understood for their roles in early development are also known to be involved in tissue maintenance and adult energy homeostasis. Furthermore, dysfunction of these signaling pathways results in human diseases such as cancer. An in depth understanding of how developmentally important signaling pathways function in the adult will provide mechanistic insights into disease and potential new therapeutic targets. Here in Chapter 1, the Wnt, fibroblast growth factor (FGF), and Hedgehog (Hh) signaling pathways are discussed and examples of their relevance in development, adult homeostasis, and disease are provided. Wnt signaling provides an example of this concept as it has well described roles during both development and adult metabolism. Work included in Chapter 2, investigates the regulation of adult energy homeostasis by a member of the endocrine FGF family, FGF19. The three endocrine FGFs, FGF19 (FGF15 in mice), FGF21, and FGF23 have well described roles in the regulation of metabolic processes in adults. While FGF23 is primarily involved in the regulation of phosphate and vitamin D homeostasis, FGF19 and FGF21 have shown similar pharmacological effects on whole body metabolism. Here, the importance of adaptive thermogenesis for the pharmacological action of FGF19 is explored. Using UCP1KO animals we show that whole-body thermogenesis is dispensable for body weight loss following FGF19 treatment. Finally, the potential involvement of Hh signaling in mediating the hyperphagia driven obesity observed in certain ciliopathies is explored in Chapter 3. Emerging evidence suggests cilia play an important role in the regulation of feeding behavior. In mammals, the hedgehog pathway is dependent on the primary cilium as an organizing center and defects in hedgehog signaling share some clinical symptoms of ciliopathies. Here, we characterized the expression of core pathway components in the adult hypothalamus. We show that neurons within specific nuclei important for regulation of feeding behavior express Hh ligand and members of its signaling pathway. We also demonstrate that the Hh pathway is transcriptionally upregulated in response to an overnight fast. This work provides an important foundation for understanding the functional role of Hh signaling in regulation of energy homeostasis. In its entirety, this work highlights the emerging clinical relevance of developmentally critical pathways in diseases associated with dysfunction of adult tissue homeostasis, such as obesity.
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    Effects of Hydrocephalus on Rodent Optic Nerve and Optic Disc
    (2021-08) McCue, Rachel A.; Belecky-Adams, Teri; Blazer-Yost, Bonnie; Mao, Weiming; Baucum, A.J.; Berbari, Nick
    Hydrocephalus affects 1 in 1,000 newborns and nearly 1,000,000 Americans, leading to an increase in intercranial pressure due to the build-up of cerebrospinal fluid. There are numerous complications that arise as a result of hydrocephalus, but this study focuses on optic disc edema. The subarachnoid space surrounding the optic nerve contains cerebrospinal fluid. The cerebrospinal fluid increases in hydrocephalus, putting pressure on the optic nerve. The additional intracranial pressure has been proposed to cause axoplasmic stasis within the retinal ganglion cell axons, leading to axonal damage and retinal ischemia. The purpose of this study was to determine the effects of hydrocephalus on the optic disc and retina in several animal models of hydrocephalus. This study uses two genetic and two injury-induced models of hydrocephalus in addition to immunohistochemistry and histological stains to examine the optic disc, thickness of retinal layers, and numbers of retinal cells. This study serves as preliminary work to help build the case that hydrocephalus causes cell loss in the retina, as well as swelling of the retinal ganglion cell axons, leading to axoplasmic stasis and cell death.
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    Investigating the Modulation of Voltage-Gated Sodium Channel Nav1.1 Neuronal Excitability by Fibroblast Growth Factor Homologous Factor 2 and Il-6
    (2023-12) Frazee, Ashley; Cummins, Theodore; Berbari, Nicolas; Baucum, A.J.; Boehm, Stephen
    Migraine is a condition that has affected many for generations and yet remains poorly understood. Mutations to the Nav1.1 voltage gated sodium channels have been implicated in various diseases such as Familial Hemiplegic Migraine 3 (FHM3), epilepsy, and autism spectrum disorder (ASD). Various proteins have been found to modify the function of these channels. Fibroblast growth factor homologous factors (FHFs) have been found to regulate the activity of some voltage-gated sodium channels (Navs). More work is needed to determine which FHFs affect which Navs. Here I looked at FHF2A and FHF2B in Nav1.1 as well as an FHM3-causing mutation to this channel, F1774S. I found that FHF2A, but not 2B, induced long-term inactivation (LTI) in the wild-type (WT) Nav1.1 and that FHF2A induced LTI in the F1774S mutant channel to a greater extent. Several changes in channel function caused by the mutation were attenuated with the addition of FHF2A, including persistent currents, leading to a possible rescue in the mutant phenotype. By contrast, the P1894L mutation, which has been found to cause ASD, greatly attenuated LTI and other impacts of FHF2A on Nav1.1. The inflammatory cytokine IL-6 was also investigated as a possible modulator of the Nav1.1 channel. There does not appear to be any direct interaction between this cytokine and the channel. Overall, my data shows for the first time that FHF2A, but FHF2B or IL-6, might be a significant modulator of Nav1.1 and can differentially modulate disease mutations.
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    Mechanisms and consequences of regulating neurabin and spinophilin's interaction with the tumor suppressor protein p140CAP
    (2017) Kaur, Harjot; Baucum, A.J.
    Glioblastoma is the most aggressive type of brain cancer with very poor prognosis. Due to the lack of understanding of underlying mechanisms, there are no anti-invasive clinical therapeutics available. SRC terminal kinase (SRC) is a tumorigenic protein that is highly expressed in glioblastoma samples. SRC inhibitor kinase 1 (SRCIN1), also known as p140Cap is a negative regulator of SRC. Silencing SRCIN1 results in increased tumor invasion. Our lab has discovered two novel scaffolding proteins Spinophilin (Spn) and neurabin (Nrb) that bind to SRCIN1. They may play a role in regulating SRCIN1 activity, as well as its downstream effects that ultimately decrease SRC’s tumorigenic activity. Spn and Nrb are two scaffolding proteins that are heavily expressed in the central nervous system. Spn knockout mice develop more tumors, indicating that Spn acts as a tumor suppressor protein, although the mechanisms of Spn’s anti-tumor properties are not well understood. Spn and Nrb are PP1 targeting proteins that target PP1 to other substrates, resulting in dephosphorylation and alteration of function. We found that PP1 increases Spn association with SRCIN1, but decreases Nrb association with SRCIN1, indicating that the two proteins might have opposite effects to balance the activity of p140Cap. We also found that cyclin-dependent kinase 5 (CDK5) phosphorylates and regulates the association of these scaffolding proteins with the tumor suppressor protein, p140Cap. Understanding these mechanisms provides insight into new therapeutic targets that may ultimately decrease SRC activity and its tumorigenic and invasive properties.
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    Phosphorylation State-Dependent Regulation of SAPAP3 and mGluR5 Association
    (Office of the Vice Chancellor for Research, 2015-04-17) Morris, Cameron; Baucum, A.J.; Edler, Mike
    This study aims to characterize the interaction between SAP90/PSD-95-associated protein 3 (SAPAP3) and metabotropic Glutamate Receptor 5 (mGluR5); specifically focusing on how SAPAP3 phosphorylation state modulates association. SAPAP3 is a scaffolding protein localized to the postsynaptic density (PSD) of striatal neurons and SAPAP3 knockout mice have Obsessive-Compulsive Disorder-like symptoms. Here, we hypothesize that spinophilin modulates SAPAP3 phosphorylation and alterations in SAPAP3 phosphorylation regulate SAPAP3 binding to mGluR5. We will use in vitro and ex vivo studies to characterize the interaction between spinophilin and SAPAP3 and to determine the functional implications of SAPAP3 phosphorylation on mGluR5 binding. These data will enhance our understanding of molecular mechanisms that regulate SAPAP3 and mGluR5 function, two proteins with known roles in obsessive-compulsive disorder.
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    The Role of TGF-B Activated Kinase (TAK1) in Retinal Development and Inflammation
    (2021-08) Carrillo, Casandra; Belecky-Adams, Teri; Baucum, A.J.; Berbari, Nicolas
    Transforming growth factor β-activated kinase 1 (TAK1), a hub kinase at the convergence of multiple signaling pathways, is critical to the development of the central nervous system and has been found to play a role in cell death and apoptosis. TAK1 may have the potential to elucidate mechanisms of cell cycle and neurodegeneration. The Belecky-Adams laboratory has aimed to study TAK1 and its potential roles in cell cycle by studying its role in chick retinal development as well as its possible implication in the progression of diabetic retinopathy (DR). Chapter 3 includes studies that explore TAK1 in a study in chick retinal development and TAK1 in in vitro studies in retinal microglia. Using the embryonic chick, immunohistochemistry for the activated form of TAK1 (pTAK1) showed localization of pTAK1 in differentiated and progenitor cells of the retina. Using an inhibitor or TAK1 activite, (5Z)-7-Oxozeaenol, in chick eye development showed an increase in progenitor cells and a decrease in differentiated cells. This study in chick suggests TAK1 may be a critical player in the regulation of the cell cycle during retinal development. Results from experimentation in chick led to studying the potential role of TAK1 in inflammation and neurodegeneration. TAK1 has previously been implicated in cell death and apoptosis suggesting that TAK1 may be a critical player in inflammatory pathways. TAK1 has been implicated in the regulation of inflammatory factors in different parts of the CNS but has not yet been studied specifically in retina or in specific retinal cells. Chapter 2 includes studies from the Belecky-Adams laboratory of in vitro work with retinal microglia. Retinal microglia were treated with activators and the translocation to the nucleus of a downstream factor of TAK1 was determined: NF-kB. Treatment of retinal microglia in the presence of activators with TAKinib, an inhibitor of TAK1 activation, revealed that TAK1 inhibition reduces the activation of downstream NF-kB. Together this data suggests that TAK1 may be implicated in various systems of the body and further studies on its mechanisms may help elucidate potential therapeutic roles of the kinase.