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EFFECTS OF BRAIN-DERIVED NEUROTROPHIC FACTOR AND ITS SIGNALING PATHWAY ON SENSORY NEURONAL ACTIVATION DURING COLITISHashmi, Fiza 01 January 2015 (has links)
Visceral hypersensitivity is the heightened response to sensory stimuli. Visceral sensations are transmitted through primary afferent neurons in the dorsal root ganglion (DRG) and the sensitization of the neural pathway leads to modification in spinal ascending and descending neurons. The aim of this investigation is to determine the effects of brain-derived neurotrophic factor (BDNF) and its signaling pathway on sensory neuronal activation during colitis. In order to evaluate this, levels of calcitonin-gene related peptide (CGRP), a neuropeptide marker for nociceptive transmission, and phosphorylated cAMP-response element binding protein (pCREB), a molecular switch in neuronal plasticity, were studied in response to BDNF in vivo and in vitro. Colitis caused an increase in the levels of CGRP and pCREB in thoracolumbar DRG, which was attenuated by BDNF neutralizing antibody and PLC inhibitor, U73122, but not PI3K inhibitor, LY294002. BDNF-induced CGRP expression and CREB activation in DRG culture was also blocked by PLC inhibitor, U73122, but not PI3K inhibitor, LY294002, or MEK kinase inhibitor, PD98059. These results suggest a unique signaling pathway, i.e. the PLC-γ pathway, is mediating BDNF action on sensory neuronal activation during colitis.
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Language Acquisition in YOung Boy and Girls in Relation to Manual Motor Function and LateralityArcher, Lynda A. January 1985 (has links)
<p>Language acquisition in relation to sex, manual motor skill and laterality was studied in forty-nine middle class normally developing children. A longitudinal design was employed and testing was done at 18, 24 and 30 months of age. Measures of language function, motor function, lateral asymmetry and general cognitive ability were used. It was predicted that: (a) girls would perform better than boys on the language measures, (b) children who scored high on manual motor tasks would talk better, (c) handedness would not be related to language ability, and that, (d) handedness and motor asymmetries would be observed at 18 months and not change at 24 and 30 months. The girls performed better than the boys on almost all the language measures. There were no sex differences for any of the other tests given. A weak association was found between manual motor skill and language productivity, but handedness and language ability were not related. Hand preference and motor asymmetries were observed at 18 months and maintained at 24 and 30 months. These results further our understanding of language development in young children and may help the assessment and treatment of children with developmental language problems. The measurement of handedness and lateral behaviors in young children permits inferences about hemisphere specialization in the young child. The results of this research support the position that hemispheric specialization does not develop with age but is present from a very early age.</p> / Doctor of Philosophy (PhD)
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Determining the effect of knocking out microRNA-21 on subsarcolemmal and interfibrillar mitochondriaBatra, Madhur 01 January 2016 (has links)
Type 2 diabetes mellitus is a growing problem across the world and has significant pathological changes associated with it, including diabetic cardiomyopathy, wherein cardiac function is reduced. MicroRNA-21 has been shown to play a role in both the heart and diabetes so it was thought that knocking out miR-21 could have a protective effect on oxidative phosphorylation function in diabetic mice. Subsarcolemmal and interfibrillar mitochondria were isolated from adult male WT, miR-21 KO, db/db, and double knockout mice (db/db and miR-21 KO cross) and evaluated for function. Knocking out miR-21 in diabetic mice showed a restorative effect in Complex I and Complex II function even though it increased ROS production in Complex I and did not show a significant change in MPTP opening. Knocking out miR-21 could potentially restore oxidative phosphorylation function in diabetic patients but at the expense of producing more ROS.
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GLOBAL-SCALE ANALYSIS OF THE DYNAMIC TRANSCRIPTIONAL ADAPTATIONS WITHIN SKELETAL MUSCLE DURING HYPERTROPHIC GROWTHKirby, Tyler 01 January 2015 (has links)
Skeletal muscle possesses remarkable plasticity in responses to altered mechanical load. An established murine model used to increase mechanical load on a muscle is the surgical removal of the gastrocnemius and soleus muscles, thereby placing a functional overload on the plantaris muscle. As a consequence, there is hypertrophic growth of the plantaris muscle. We used this model to study the molecular mechanisms regulating skeletal muscle hypertrophy.
Aged skeletal muscle demonstrates blunted hypertrophic growth in response to functional overload. We hypothesized that an alteration in gene expression would contribute to the blunted hypertrophic response observed with aging. However, the difference in gene expression was modest, with cluster analysis showing a similar pattern of expression between the two groups. Despite ribosomal protein gene expression being higher in the aged group, ribosome biogenesis was significantly lower in aged compared with young skeletal muscle in response to the hypertrophic stimulus (50% versus 2.5-fold, respectively). The failure to fully up-regulate pre-47S ribosomal RNA (rRNA) expression in old skeletal muscle undergoing hypertrophy indicated ribosomal DNA transcription by RNA polymerase I was impaired. Contrary to our hypothesis, the findings of the study suggest that impaired ribosome biogenesis was a primary factor underlying the blunted hypertrophic response observed in old skeletal muscle rather than dramatic differences in gene expression.
As it appears ribosomal biogenesis may limit muscle hypertrophy, we assessed the dynamic changes in global transcriptional output during muscle hypertrophy, as the majority of global transcription is dedicated to ribosome biogenesis during periods of rapid growth. Metabolic labeling of nascent RNA using 5-ethynyl uridine permitted the assessment of cell type specific changes in global transcription and how this transcription is distributed within the myofiber. Using this approach, we demonstrate that myofibers are the most transcriptionally active cell-type in skeletal muscle, and furthermore, myonuclei are able to dramatically upregulate global transcription during muscle hypertrophy. Interestingly, the myonuclear accretion that occurs with hypertrophy actually results in lower transcriptional output across nuclei within the muscle fiber relative to sham conditions. These findings argue against the notion that nuclear accretion in skeletal muscle is necessary to increase the transcriptional capacity of the cell in order to support a growth response.
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Role of Translation Initiation in Regulation of Epithelial Junctions and Cell MotilityAlsharief, Fahda Fawaz 01 January 2017 (has links)
The integrity and barrier properties of intestinal epithelium are determined by specialized adhesive structures known as intercellular junctions; composed of adherens junctions (AJs), tight junctions (TJs) and focal adhesions that mediate cell-cell and cell matrix interactions, respectively. These two types of epithelial cell adhesions regulate each other during disruption and restitution of the epithelial barrier. Inflammatory cytokines such as interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) are elevated during intestinal inflammation. The most notable effects of IFNγ and TNFα on intestinal epithelial homeostasis involve disruption of apical junctions and attenuation of cell migration. Although molecular mechanisms underlying these effects remain poorly understood, expressional downregulation of different adhesion proteins may play a major role in the cytokine-dependent disruption of the intestinal epithelial barriers. This thesis is based on the hypothesis that inhibition of the protein translation initiation machinery promotes the disruption of the intestinal epithelial barrier and attenuates epithelial restitution during mucosal inflammation. This study was focused on two eukaryotic translation initiation factors, eIF4G1 and eIF4G2, which play essential roles in the regulation of cap-dependent protein translation. Expression of both translation initiation factors was dramatically downregulated in model intestinal epithelial cell monolayers treated with IFNγ and TNFα in parallel to cytokine-induced disruption of the epithelial barrier. siRNA or shRNA-mediated downregulation of either eIF4G1, or eIF4G2 increased permeability of well-differentiated SK-CO15 intestinal epithelial cell monolayers and decreased expression of different adherens junction and tight junction proteins. Furthermore depletion of these translation initiating factors inhibits different modes of migration (wound healing and transfilter migration) of stem-cell like and well-differentiated intestinal epithelial cells. These findings suggest that eukaryotic translation initiation factors of the eIF4G family play unique roles in regulating integrity and restitution of the intestinal epithelial barrier. Downregulation of these translation initiating factors may mediate disruption of the intestinal epithelial barriers during mucosal inflammation.
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THE EFFECT OF ALCOHOL CONSUMPTION ON FEMALE INFLAMMATIONDeGroat, Ashley R., Peterson, Jonathan M. 05 April 2018 (has links)
INTRODUCTION: Alcoholic cirrhosis occurs at a higher rate in female patients, at an earlier age, and with a lower consumption of alcohol compared to male patients. In our study on alcoholic fatty liver disease (AFLD) and adipokine levels, female mice showed a 50% higher mortality rate compared to ethanol fed male mice. The amount of ethanol consumed was similar between sexes when normalized to body weight. This resulted in our hypothesis that female mice are more susceptible to inflammation caused by alcohol consumption. METHODS: 12-week old female mice were fed a Lieber-Decarli alcohol diet (5% ETOH by volume) for 6-weeks and body weight and food intake were measured daily. Serum was collected from the mice and alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum triglycerides, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) levels were measured with the appropriate assays. RESULTS: In response to alcohol feeding, female mice showed significant increases in levels of ALT and AST compared to the male mice, indicating increased damage to the liver. TNF-α and IL-6 were also significantly increased in the ethanol fed female mice, indicating a significant increase in inflammation compared to the male ethanol fed mice. There was no difference found in the levels of serum triglycerides. CONCLUSION: These results indicate chronic alcohol consumption affects mice in a sex dependent manner, and that female mice are more susceptible to the adverse effects of alcohol than male mice. Increased female susceptibility to ethanol-induced damage must be considered in future ethanol-feeding studies.
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UPREGULATING OF CYP2E1 IN ETHANOL-FED MICE WITH TRANSGENIC OVEREXPRESSION OF CTRP3Warren, Zachary C, Peterson, Jonathan M 05 April 2018 (has links)
INTRODUCTION: The liver is the primary organ responsible for the removal of toxic substances from the body by means of a variety of metabolic pathways. One class of proteins responsible for much of the body’s xenobiotic drug and alcohol metabolism is the Cytochrome P450 family of proteins. One protein, Cytochrome P450 Class E Subclass 2 (Cyp2E1), has an integral role in alcohol metabolism by the liver. Cyp2E1 becomes fully activated after an organism has consumed excessive amounts of alcohol excessive alcohol and works with aldehyde dehydrogenase (ALDH) to metabolize ethanol to acetaldehyde. Another metabolic protein, C1q TNF Related Protein 3 (CTRP3), has been shown to effectively prevent alcoholic fatty liver disease (AFLD), specifically with long-term alcohol-induced lipid accumulation.
METHODS: In this experiment, 12-week old male mice were fed a Lieber-Decarli alcohol diet (5% ETOH by volume) for 6-weeks. The food intake and body weight of the mice was recorded each day. The mice in the experiment included both wild type and transgenic CTRP3 overexpressing mice. At the end of the 6-week period the mice were euthanized, and the liver was carefully removed, flash-frozen, and prepared for immunoblot analysis of the proteins.
RESULTS: Cyp2E1 levels increased significantly in response to ethanol consumption. Cyp2E1 levels were further elevated in ethanol-fed CTRP3 transgenic overexpressing mice. Cyp2E1 levels in CTRP3 transgenic mice were nearly twice that of wild type ethanol-fed mice.
CONCLUSIONS: The results of the experiment show a significant increase in Cyp2E1 in mice which overexpress CTRP3. This upregulation of Cyp2E1 with CTRP3 overexpression could explain the mechanism for reduced hepatic lipid accumulation in ethanol-fed CTRP3 transgenic mice.
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SEX DIFFERENCES IN CELL DEATH AND STEROID HORMONE RECEPTORS IN CORTICAL EXPLANTSTrout, Amanda L 01 January 2013 (has links)
Estrogens, such as the biologically active 17-b estradiol (E2) have many actions in the male and female brain. Not only does E2 regulate reproductive behavior in adults, it organizes and activates the brains of younger animals in a sex-specific manner. In addition, many human studies have shown E2 to provide protection against a variety of neurological disorders, including stoke. These studies have been controversial and depend largely on the type and timing of hormone replacement. Animal studies are much less controversial and clearly demonstrate a neuroprotective role for E2 following ischemic brain injury. Because much of E2 neuroprotection requires sex steroid hormone receptors, it is essential to understand expression patterns of these receptors. For the current studies, I evaluated estrogen receptor alpha (ER α), estrogen receptor beta (ER β) and androgen receptor (AR) expression in the cortex. It is known that these receptors change in expression at several times in an animal’s life span including during early postnatal development and following ischemic brain injury. Here I used an in vitro cortical explant model to further examine how these receptors change both during development and following injury. This in vitro model is important because it provides a way to investigate changes in receptor expression pattern in the cortex without input from other brain regions. In addition to characterizing this model, I also evaluated the contribution of E2 to changes in receptor expression and on cell death following injury in the explants. To begin to decipher mechanisms for E2 mediated neuroprotection, I added antagonist for each of the receptors before and after injury. In each these experiments, I also examined potential sex differences by separating the female and male brains before I cultured the explants. Overall, these experiments showed that cortical explants are a good in vitro model. Here we found that E2 was protective in female, but not male cortical explants following injury. However, the exact mechanisms of E2-mediated neuroprotection are still to be deciphered.
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PHYSIOLOGICAL AND TOXICOLOGICAL ROLES OF ABC TRANSPORTERS IN CELLULAR EFFLUX OF SUBSTRATESCoy, Donna J 01 January 2012 (has links)
ATP-binding cassette (ABC) transporters are transmembrane proteins that transport a wide variety of substrates across intra and extra-cellular membranes. A few examples of endo and xenobiotic substrates are metabolic products, lipids, sterols, and drugs. An important function of ABC transporters involved in export is to prevent intracellular the buildup of toxic products. Several ABC transporters have also been associated with drug resistance upon treatment with chemotherapeutic agents. P-glycoprotein (P-GP) and the multidrug resistant (MRP) transporters of the ABC C family are examples of transporters that confer chemo-resistance.
We have studied two unique roles of ABC transporters in the liver and the heart. In the liver, maintenance of bile secretion is important during lactation to ensure proper absorption of nutrients for the offspring. Three main ABC transporters are involved in this process: ABCB11 (transports bile acids), ABCB4 (transporters phospholipids), and ABCG5/ABCG8 (transports cholesterol). In the rat, expression of ABCB11 remains the same as the size of the bile acid pool increases. However, the expression of ABCG5/ABCG8 is abolished, preventing excessive export and loss of cholesterol from the liver. The regulation of these transporters during lactation maintains the production of bile acids from cholesterol by decreasing export while preventing toxicity from bile acids by maintaining bile flow.
Another protective role of ABC transporters is seen in oxidative stress-induced toxicity of cardiac tissue following treatment with Doxorubicin (DOX), a drug used in cancer treatment. Multidrug resistance protein 1 (Mrp1) can transport toxic products by conjugation with sulfate, glutathione (GSH) or glucuronide. In Mrp1-/- mice, DOX causes advanced cell damage through intracellular edema and increased apoptotic nuclei. However, P-glycoprotein expression increases upon DOX treatment, potentially compensating for the loss of Mrp1. Mrp1 can also transport GSH, GSH disulfide (GSSG), and products of oxidation, like GSH conjugates. In the absence of Mrp1, GSH levels are increased in the heart, providing protection against oxidative stress.
Both of these examples in liver and heart show the diversity of ABC transporters and the role they play in preventing cell toxicity. These studies also provide insight into ways to prevent cell toxicity through manipulation of ABC transport proteins.
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TARGETING MALADAPTIVE PLASTICITY AFTER SPINAL CORD INJURY TO PREVENT THE DEVELOPMENT OF AUTONOMIC DYSREFLEXIAEldahan, Khalid C. 01 January 2019 (has links)
Vital autonomic and cardiovascular functions are susceptible to dysfunction after spinal cord injury (SCI), with cardiovascular dysregulation contributing to morbidity and mortality in the SCI population. Autonomic dysreflexia (AD) is a condition that develops after injury to the sixth thoracic spinal segment or higher and is characterized by potentially dangerous and volatile surges in arterial pressure often accompanied with irregular heart rate, headache, sweating, flushing of the skin, and nasal congestion. These symptoms occur in response to abnormal outflow of sympathetic activity from the decentralized spinal cord typically triggered by noxious, yet unperceived nociceptive stimulation beneath the level of lesion. Maladaptive plasticity of primary afferents and spinal interneurons influencing sympathetic preganglionic neurons is known to contribute to the development of AD. However, there are currently no treatments capable of targeting this underlying pathophysiology. The goal of this work was to test pharmacological agents for their potential to modify intraspinal plasticity associated with AD in order to prophylactically prevent the development of this condition altogether.
We first tested whether the drug rapamycin (RAP), a well-studied inhibitor of the growth promoting kinase “mammalian target of rapamycin” (mTOR), could prevent aberrant sprouting of primary c-fiber afferents in association with reduced indices of AD severity. Naïve and T4-transected rats undergoing 24/7 cardiovascular monitoring were treated with rapamycin (i.p.) for 4 weeks before tissue collection. RAP attenuated intraspinal mTOR activity after injury, however it also caused toxic weight loss. RAP treated SCI rats developed abnormally high blood pressure both at rest and during colorectal distension (CRD) induced AD, as well as more frequent bouts of spontaneous AD (sAD). These cardiovascular alterations occurred without altered intraspinal c-fiber sprouting. Our finding that rapamycin exacerbates cardiovascular dysfunction after SCI underscores the importance of screening potential pharmacological agents for cardiovascular side effects and suggests that the mTOR pathway plays a limited or dispensable role in c-fiber sprouting after SCI.
We next examined the effects of the antinociceptive drug gabapentin (GBP) on AD development. Our previous work demonstrated that a single acute administration of GBP can reduce the severity of AD. The mechanism of action, however, remains unclear. Emerging evidence suggests that GBP may act by blocking de novo synaptogenesis. We investigated whether continuous GBP treatment could attenuate the development of AD by modifying synaptic connectivity between primary afferents and ascending propriospinal neurons. SCI rats were treated with GBP every six hours for four weeks. We found that GBP reduced blood pressure during CRD stimulation and prevented bradycardia typically observed during AD. However, GBP treated rats also had a higher sAD frequency and failed to return to pre-injury body weight. Moreover, SCI reduced the density of putative excitatory (VGLUT2+) and inhibitory (VGAT+) synaptic puncta in the lumbosacral cord, although GBP did not alter these parameters. Our results suggest that continuous GBP treatment alters hemodynamic control after SCI and that decreased synaptic connectivity may contribute to the development of AD.
These studies demonstrate the need for further research to better understand the cellular signaling driving maladaptive plasticity after SCI as well as the complex and dynamic changes in intraspinal synaptic connectivity contributing to the development of AD. Moreover, GBP treatment may offer clinical benefit by reducing blood pressure during AD, however the optimal dosage must be identified to avoid undesired side-effects.
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