1,720,978 research outputs found
Calcineurin as a Potential Target of TRPM7 Signaling in Migration and Invasion of Glioblastoma Cells
Get PDFTransient receptor potential melastatin 7 (TRPM7) is a divalent cation channel that plays critical roles in various cancers including glioblastoma (GBM), the most malignant brain tumor in adults. As modulation of TRPM7 activity affects GBM cell behaviors, better understanding of this pathway could reveal novel therapeutic targets. Calcineurin, a Ca2+-dependent phosphatase, is also crucial for GBM cell survival and migration. Although it may potentially interact with TRPM7, this possibility has not been explored. To address whether calcineurin contributes to TRPM7 signaling in GBM cells, I showed an interaction between TRPM7 and calcineurin proteins, which may be direct or within a protein complex. TRPM7 is suggested to function upstream instead of downstream from calcineurin, which implicates calcineurin as a potential mediator of TRPM7 signaling. In summary, calcineurin interacts with TRPM7 and is suggested to mediate the TRPM7 signaling pathway as a downstream target in glioblastoma cell migration and invasion.M.Sc.2022-06-22 00:00:0
Transient Receptor Potential Melastatin 7 Channel Affects Neurite Outgrowth of Hippocampal Neurons in vitro
Get PDFCentral Nervous System (CNS) neurons are highly specialized cells that assemble into functional networks by extending their axons and dendrites. Transient Receptor Potential Melastatin 7 (TRPM7) is a stretch-activated, calcium permeable non-selective cation channel that has previously been shown to be involved in cellular processes that are important for neurite elongation, such as vesicle fusion and cell adhesion by modulating cytoskeletal dynamics. The present study investigates the role of TRPM7 in neurite outgrowth using genetic and pharmacological approaches on cultured mouse hippocampal neurons. Both shRNA knockdown of endogenous TRPM7 expression and blocking of TRPM7 channel function using carvacrol resulted in enhanced neurite elongation, suggesting that TRPM7 may negatively regulate neurite outgrowth process during neuronal development. Co-immunoprecipitation data suggest that TRPM7 may be involved in neurite outgrowth process by modulating actin cytoskeletal dynamics via alpha-actinin-1.MAS
Cellular and Molecular Mechanisms of Transient Receptor Potential Melastatin 7 (TRPM7) Channel in Neuronal Development and Injury
Get PDFTransient Receptor Potential Melastatin 7 (TRPM7) is a ubiquitously expressed, calcium-permeable ion channel that regulates intracellular levels of divalent cations, cytoskeletal dynamics, cell adhesion and other processes. As these processes are critical for neurite elongation during development, this thesis investigated the role of TRPM7 in neurite outgrowth and development using a pharmacological approach. It was found that blocking TRPM7 activity preferentially enhanced axonal outgrowth of cultured hippocampal neurons at least in part through TRPM7 interaction with cytoskeletal proteins, actin and α-actinin. TRPM7 activity is potentiated under the conditions of stress that commonly occur in injury or disease, such as increased extracellular acidity and production of reactive oxygen species. Therefore, the effect of hypoxia, a common cause of damage to the developing brain, on TRPM7 activity and TRPM7-mediated neurite outgrowth was investigated next. It was found that prolonged hypoxia caused axonal retraction, while blocking TRPM7 activity attenuated this effect. Finally, the therapeutic potential of TRPM7 blocker has been evaluated in a mouse model of neonatal hypoxic-ischemic brain injury, and blocking TRPM7 pharmacologically had neuroprotective and therapeutic effects (up to 1 hour after injury). Further short and long-term evaluation demonstrated preservation of brain morphology and functional motor and memory outcomes. Proteomic analysis revealed that TRPM7 may mediate neuronal injury at least in part through calcium-dependent cytoskeletal regulation by calcium/calmodulin-dependent kinase and phosphatase. Overall, this thesis establishes the role of TRPM7 in neuronal outgrowth and development under normal and stress conditions. Moreover, it evaluates a specific pharmacological inhibitor of TRPM7 as a candidate for further drug development for hypoxic-ischemic injury to the developing brain.Ph.D.2020-11-19 00:00:0
Effects of TRPM2 Inhibition in Neuroprotection following Neonatal Hypoxic-Ischemic Brain Injury
Get PDFNeonatal hypoxic-ischemic (HI) brain injury is a major cause of acute mortality and chronic neurological morbidity in infants and children. Studies indicate that transient receptor potential melastatin 2 or TRPM2 (a non-selective cation channel with high permeability to calcium that can be activated by intracellular adenosine diphosphoribose [ADPR] and H2O2) can mediate neuronal death following acute ischemic insults in adult mice as well as HI brain injury in neonatal mice. My study tested the effect of a newly described TRPM2 channel inhibitor AG490 by using a H2O2-induced neuronal cell death in vitro model and mouse HI brain injury in vivo model. I found that the inhibition of TRPM2 channels by AG490 demonstrates a neuroprotective effect both in vitro and in vivo. The neuroprotective effect of AG490 following post-injury treatment suggests the potential clinical implications of this drug, including the possible prevention of HI related neurological complications such as hypoxic-ischemic encephalopathy.M.Sc.2019-11-07 00:00:0
Transient Receptor Potential Melastatin 7 Channel Affects Neurite Outgrowth of Hippocampal Neurons in vitro
No full textCentral Nervous System (CNS) neurons are highly specialized cells that assemble into functional networks by extending their axons and dendrites. Transient Receptor Potential Melastatin 7 (TRPM7) is a stretch-activated, calcium permeable non-selective cation channel that has previously been shown to be involved in cellular processes that are important for neurite elongation, such as vesicle fusion and cell adhesion by modulating cytoskeletal dynamics. The present study investigates the role of TRPM7 in neurite outgrowth using genetic and pharmacological approaches on cultured mouse hippocampal neurons. Both shRNA knockdown of endogenous TRPM7 expression and blocking of TRPM7 channel function using carvacrol resulted in enhanced neurite elongation, suggesting that TRPM7 may negatively regulate neurite outgrowth process during neuronal development. Co-immunoprecipitation data suggest that TRPM7 may be involved in neurite outgrowth process by modulating actin cytoskeletal dynamics via alpha-actinin-1.MAS
Transient Receptor Potential Melastatin 2 (TRPM2) Channel Plays a Role in Neonatal Hypoxic-ischemic Brain Injury
No full textRecent advances in stroke research have identified non-glutamate mechanisms associated with ischemic neuronal death in adults. Among the molecules involved in non-glutamate mechanisms, transient receptor potential melastatin 2 (TRPM2), a calcium-permeable non-selective cation channel, is reported to mediate brain damage following ischemic insults in adult mice. However, the role of TRPM2 channels in neonatal hypoxic-ischemic brain injury remains unknown. Here, we propose that TRPM2-null mice (TRPM2+/- and TRPM2-/-) reduces neonatal hypoxic-ischemic brain injury in postnatal 7-day-old mice. We report that the infarct volumes are significantly smaller and behavioral outcomes are improved in neonatal TRPM2+/- and TRPM2-/- mice compared to wild type mice. Next, we found that TRPM2-null mice down-regulated GSK-3β activity following HI. We subsequently tested the role of GSK-3β in neonatal HI brain injury using the pharmacological blocker TDZD-8. We showed that GSK-3β activity is involved in apoptotic neuronal cell death that could link the Akt/GSK-3β/caspase-3 pathway.M.Sc.2018-12-05 00:00:0
Role of Ion Channels in Glioblastoma
Get PDFGlioblastoma (GBM) accounts for the majority of astrocytic tumours and represents the most common primary brain cancer. Prognosis for patients is dismal even with aggressive treatment. Because of diffused GBM invasion throughout the brain, it is impossible for surgery to completely remove the tumour. Chemotherapeutic adjuvants are used in attempt to eradicate remnant GBM cells. Unfortunately, the standard clinically used drugs have limited therapeutic benefits. Thus, there is need to identify novel drug targets.
Although ion channels contribute to a wide array of fundamental cellular functions, the role of ion channels in GBM is ill-defined. A better understanding of ion channels can potentially present new effective ways to treat GBM. In this thesis, I aimed to fill some of these knowledge gaps by investigating two exciting candidates: the transient receptor potential melastatin 7 (TRPM7), and the swelling induced chloride current (ICl,swell), both of which can potentially serve as cellular "sensors" for key GBM characteristics such as hypoxia and cell volume.
In my first aim, I validated the involvement of TRPM7 in GBM cellular functions and the underlying signalling by employing a unique experimental approach. That is, I found that pharmacologically potentiating TRPM7 enhanced GBM motility. In my second aim, I evaluated the therapeutic potential of the specific TRPM7 antagonist waixenicin A. By employing both in vitro and in vivo approaches, I provided evidence suggesting that waixenicin A reduced GBM cellular functions. Lastly, in my third aim, I expanded my scope of study in order to gain a broader understanding of ion channels' roles in GBM by examining ICl,swell, a target that may complement TRPM7 in various physicochemical sensory roles. Here, I observed that inhibiting ICl,swell can also suppress GBM cellular functions. Overall, the objective of my thesis is to elucidate the ill-defined roles of TRPM7 and ICl,swell in GBM in order to identify potential targets for pursuit of further drug development.Ph.D.2022-11-30 00:00:0
Transient Receptor Potential Melastatin 2 (TRPM2) Channel Plays a Role in Neonatal Hypoxic-ischemic Brain Injury
Get PDFRecent advances in stroke research have identified non-glutamate mechanisms associated with ischemic neuronal death in adults. Among the molecules involved in non-glutamate mechanisms, transient receptor potential melastatin 2 (TRPM2), a calcium-permeable non-selective cation channel, is reported to mediate brain damage following ischemic insults in adult mice. However, the role of TRPM2 channels in neonatal hypoxic-ischemic brain injury remains unknown. Here, we propose that TRPM2-null mice (TRPM2+/- and TRPM2-/-) reduces neonatal hypoxic-ischemic brain injury in postnatal 7-day-old mice. We report that the infarct volumes are significantly smaller and behavioral outcomes are improved in neonatal TRPM2+/- and TRPM2-/- mice compared to wild type mice. Next, we found that TRPM2-null mice down-regulated GSK-3β activity following HI. We subsequently tested the role of GSK-3β in neonatal HI brain injury using the pharmacological blocker TDZD-8. We showed that GSK-3β activity is involved in apoptotic neuronal cell death that could link the Akt/GSK-3β/caspase-3 pathway.M.Sc.2018-12-05 00:00:0
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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