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You searched for +publisher:"Temple University" +contributor:("Ferguson, Tanya;"). Showing records 1 – 3 of 3 total matches.

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Temple University

1. Srivastava, Isha Narain. The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy.

Degree: PhD, 2017, Temple University

Biomedical Neuroscience

Background and Purpose –The mammalian target of rapamycin (mTOR) pathway has been implicated in cellular responses to hypoxia and inflammation. Cerebral palsy (CP) is a neurodevelopmental disorder often linked to hypoxic and inflammatory injury to the brain, however, a role for mTOR modulation in CP has not been investigated. We hypothesized that mTOR inhibition would prevent neuronal death and diminish inflammation in a mouse model of CP. Methods – Post-natal day 6 mouse pups were subjected to hypoxia-ischemia and lipopolysaccharide-induced inflammation (HIL), a model of CP causing injury to several brain areas. Mice received rapamycin (5mg/kg) following HIL, and then daily for 3 subsequent days. The phospho-activation of the mTOR effector mTOR effector proteins S6, S6K and 4EBP as well as upstream negative regulators, TSC1 and Redd1, were assessed as an in vivo measure of the mTOR signaling cascade. Expression of hypoxia inducible factor 1 (HIF-1 alpha) was assayed as an indicator of hypoxia-mediated cellular injury. Neuronal cell death was defined with Fluoro-Jade C (FJC) and cleaved-caspase 3 (CC3), a marker of apoptosis. Autophagy was measured using Beclin-1 and LC3II expression. Lastly, neuroninflammation following HIL was evaluated by examining Iba-1 labeled microglia number and morphology, as well as P-STAT3 expression. Results – Neuronal death, HIF-1alpha expression, and numerous Iba-1 labeled microglia were evident at 24 and 48 hours following HIL. Basal mTOR signaling was unchanged by HIL. Coincident with persistent mTOR signaling, a decreased in Redd1 expression but not TSC1 was observed in HIL. Increased P-STAT3 expression was observed at 24 and 48 hours post-HIL. Rapamycin treatment following HIL significantly reduced neuronal death, decreased HIF-1 alpha and P-STAT3 expression, and microglial activation, coincident with enhanced expression of Beclin-1 and LC3II, markers of autophagy induction. Increase in neuronal death was observed with concomitant administration of rapamycin and chloroquine, an autophagy inhibitor. Administration of a S6K inhibitor, PF-4708671, following HIL also decreased FJC staining further supporting an mTOR-dependent effect of HIL. Conclusions – mTOR inhibition prevented neuronal cell death and diminished neuroinflammation in this model of CP. Persistent mTOR signaling following HIL suggests a failure of autophagy induction, which may contribute to neuronal death in CP. These results suggest that mTOR signaling may be a novel therapeutic target to reduce neuronal cell death in CP.

Temple University – Theses

Advisors/Committee Members: Crino, Peter;, Selzer, Michael E., Soprano, Dianne R., Ferguson, Tanya, Valencia, Ignacio;.

Subjects/Keywords: Neurosciences;

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Srivastava, I. N. (2017). The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,346472

Chicago Manual of Style (16th Edition):

Srivastava, Isha Narain. “The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy.” 2017. Doctoral Dissertation, Temple University. Accessed September 24, 2020. http://digital.library.temple.edu/u?/p245801coll10,346472.

MLA Handbook (7th Edition):

Srivastava, Isha Narain. “The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy.” 2017. Web. 24 Sep 2020.

Vancouver:

Srivastava IN. The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy. [Internet] [Doctoral dissertation]. Temple University; 2017. [cited 2020 Sep 24]. Available from: http://digital.library.temple.edu/u?/p245801coll10,346472.

Council of Science Editors:

Srivastava IN. The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy. [Doctoral Dissertation]. Temple University; 2017. Available from: http://digital.library.temple.edu/u?/p245801coll10,346472


Temple University

2. Feather, Danielle. GLT-1 dysfunction as an underlying cause of cerebral palsy.

Degree: PhD, 2016, Temple University

Biochemistry

Cerebral Palsy (CP) is an umbrella term that describes abnormal motor movements that is caused by damage in the brain and, depending on the region(s) of the brain affected, can cause additional deficits. Roughly 30-50% of children with CP also have co-morbid cognitive impairments. The underlying insults that cause brain damage in CP are not fully understood. Research has shown that neonatal hypoxia-ischemia combined with intrauterine infection are the most common underlying causes of white matter damage (periventricular leukomalacia) and CP. Most research to date has focused on the role of oligodendrocytes due to the correlation of PVL (oligodendrocyte loss) and the development of CP. However, although oligodendrocyte loss is the prevalent brain damage noted in CP, this research has not lead to a cure; therefore, our focus has shifted toward a different cell type: astrocytes. Astrocytes maintain glutamate homeostasis through the sodium- dependent glutamate transporters, primarily GLT-1, protecting the neurons in the brain from excitotoxic injury. Our hypothesis is that underlying cellular changes, beginning with loss of astrocytes and their glutamate uptake functions through GLT-1, sets the stage for the development of CP, including: periventricular leukomalacia, neuronal cell death, and motor and cognitive deficits. To test our hypothesis, we use a neonatal mouse model of CP that combines hypoxia, ischemia, and inflammation to induce PVL and neuronal death. Using a battery of neonatal motor tests 48 hours after injury, mice with CP show significant motor deficits compared to shams. Additionally, adult mice with CP display motor deficits, indicating that this model has long lasting motor deficits and is an appropriate model to study CP. Interestingly, adult mice also display cognitive deficits, the most common co-morbid condition associated with CP Our preliminary data suggest a 6-8%, decrease in astrocytes in the ipsilateral hippocampus as early as six hours after injury and persists up to 24 hours. Similarly, there is a decrease in GLT-1 function 24 hours after injury. Interestingly, GLT-1 protein expression is not decreased in CP mice until 72 hours following injury, indicating that increased GLT-1 protein is not an early contributing factor in the observed functional changes. Neuronal cell damage is apparent 12 hours after injury and peaking at 18 hours; however, apoptosis begins 24 hours after injury, indicating that signs of neuron injury are delayed. To determine white matter injury, we examined two different white matter tracts: the corpus callosum and the pyramids in the brainstem. In both of these major white matter structures, examined in adulthood, volume is decreased. Beta-lactam compounds are known to increase GLT-1 expression and function and are neuroprotective in injury models. Furthermore, they may offer a therapeutic treatment for CP. We show that MC-100093 (093), an experimental beta-lactam developed by our colleagues, and clavulanic acid (CA), a FDA-approved beta-lactam, can…

Advisors/Committee Members: Rothberg, Brad S., Ferguson, Tanya;, Soprano, Dianne R., Giangiacomo, Kathleen, Blass, Benjamin E.;.

Subjects/Keywords: Neurosciences; Biology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Feather, D. (2016). GLT-1 dysfunction as an underlying cause of cerebral palsy. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,409354

Chicago Manual of Style (16th Edition):

Feather, Danielle. “GLT-1 dysfunction as an underlying cause of cerebral palsy.” 2016. Doctoral Dissertation, Temple University. Accessed September 24, 2020. http://digital.library.temple.edu/u?/p245801coll10,409354.

MLA Handbook (7th Edition):

Feather, Danielle. “GLT-1 dysfunction as an underlying cause of cerebral palsy.” 2016. Web. 24 Sep 2020.

Vancouver:

Feather D. GLT-1 dysfunction as an underlying cause of cerebral palsy. [Internet] [Doctoral dissertation]. Temple University; 2016. [cited 2020 Sep 24]. Available from: http://digital.library.temple.edu/u?/p245801coll10,409354.

Council of Science Editors:

Feather D. GLT-1 dysfunction as an underlying cause of cerebral palsy. [Doctoral Dissertation]. Temple University; 2016. Available from: http://digital.library.temple.edu/u?/p245801coll10,409354


Temple University

3. Srivastava, Isha Narain. The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy.

Degree: PhD, 2017, Temple University

Biomedical Neuroscience

Background and Purpose –The mammalian target of rapamycin (mTOR) pathway has been implicated in cellular responses to hypoxia and inflammation. Cerebral palsy (CP) is a neurodevelopmental disorder often linked to hypoxic and inflammatory injury to the brain, however, a role for mTOR modulation in CP has not been investigated. We hypothesized that mTOR inhibition would prevent neuronal death and diminish inflammation in a mouse model of CP. Methods – Post-natal day 6 mouse pups were subjected to hypoxia-ischemia and lipopolysaccharide-induced inflammation (HIL), a model of CP causing injury to several brain areas. Mice received rapamycin (5mg/kg) following HIL, and then daily for 3 subsequent days. The phospho-activation of the mTOR effector mTOR effector proteins S6, S6K and 4EBP as well as upstream negative regulators, TSC1 and Redd1, were assessed as an in vivo measure of the mTOR signaling cascade. Expression of hypoxia inducible factor 1 (HIF-1 alpha) was assayed as an indicator of hypoxia-mediated cellular injury. Neuronal cell death was defined with Fluoro-Jade C (FJC) and cleaved-caspase 3 (CC3), a marker of apoptosis. Autophagy was measured using Beclin-1 and LC3II expression. Lastly, neuroninflammation following HIL was evaluated by examining Iba-1 labeled microglia number and morphology, as well as P-STAT3 expression. Results – Neuronal death, HIF-1alpha expression, and numerous Iba-1 labeled microglia were evident at 24 and 48 hours following HIL. Basal mTOR signaling was unchanged by HIL. Coincident with persistent mTOR signaling, a decreased in Redd1 expression but not TSC1 was observed in HIL. Increased P-STAT3 expression was observed at 24 and 48 hours post-HIL. Rapamycin treatment following HIL significantly reduced neuronal death, decreased HIF-1 alpha and P-STAT3 expression, and microglial activation, coincident with enhanced expression of Beclin-1 and LC3II, markers of autophagy induction. Increase in neuronal death was observed with concomitant administration of rapamycin and chloroquine, an autophagy inhibitor. Administration of a S6K inhibitor, PF-4708671, following HIL also decreased FJC staining further supporting an mTOR-dependent effect of HIL. Conclusions – mTOR inhibition prevented neuronal cell death and diminished neuroinflammation in this model of CP. Persistent mTOR signaling following HIL suggests a failure of autophagy induction, which may contribute to neuronal death in CP. These results suggest that mTOR signaling may be a novel therapeutic target to reduce neuronal cell death in CP.

Temple University – Theses

Advisors/Committee Members: Crino, Peter;, Selzer, Michael E., Soprano, Dianne R., Ferguson, Tanya, Valencia, Ignacio;.

Subjects/Keywords: Neurosciences;

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Srivastava, I. N. (2017). The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,446570

Chicago Manual of Style (16th Edition):

Srivastava, Isha Narain. “The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy.” 2017. Doctoral Dissertation, Temple University. Accessed September 24, 2020. http://digital.library.temple.edu/u?/p245801coll10,446570.

MLA Handbook (7th Edition):

Srivastava, Isha Narain. “The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy.” 2017. Web. 24 Sep 2020.

Vancouver:

Srivastava IN. The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy. [Internet] [Doctoral dissertation]. Temple University; 2017. [cited 2020 Sep 24]. Available from: http://digital.library.temple.edu/u?/p245801coll10,446570.

Council of Science Editors:

Srivastava IN. The Role of Mammalian Target of Rapamycin (mTOR) in a Mouse Model of Cerebral Palsy. [Doctoral Dissertation]. Temple University; 2017. Available from: http://digital.library.temple.edu/u?/p245801coll10,446570

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