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- University of Kentucky Doctoral Dissertations (14)
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Articles 1 - 30 of 35
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A Shared Gene Expression Signature In Mouse Models Of Ebv-Associated And Non-Ebv-Associated Burkitt Lymphoma, Kathryn T. Bieging, Kamonwan Fish, Subbarao Bondada, Richard Longnecker
A Shared Gene Expression Signature In Mouse Models Of Ebv-Associated And Non-Ebv-Associated Burkitt Lymphoma, Kathryn T. Bieging, Kamonwan Fish, Subbarao Bondada, Richard Longnecker
Microbiology, Immunology, and Molecular Genetics Faculty Publications
The link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional …
P40: The Missing Link Between Autophagy And Cancer?, Mittul Patel
P40: The Missing Link Between Autophagy And Cancer?, Mittul Patel
Kaleidoscope
No abstract provided.
Diurnal Variations Of Genes Contributing To Sodium And Potassium Cardiac Currents, Parvathi Nataraj
Diurnal Variations Of Genes Contributing To Sodium And Potassium Cardiac Currents, Parvathi Nataraj
Kaleidoscope
No abstract provided.
Ghrelin Receptor Deficiency Does Not Affect Diet-Induced Atherosclerosis In Low-Density Lipoprotein Receptor-Null Mice, Kirk M. Habegger, Erin Grant, Paul Thomas Pfluger, Diego Perez-Tilve, Alan Daugherty, Dennis Bruemmer, Matthias H. Tschöp, Susanna M. Hofmann
Ghrelin Receptor Deficiency Does Not Affect Diet-Induced Atherosclerosis In Low-Density Lipoprotein Receptor-Null Mice, Kirk M. Habegger, Erin Grant, Paul Thomas Pfluger, Diego Perez-Tilve, Alan Daugherty, Dennis Bruemmer, Matthias H. Tschöp, Susanna M. Hofmann
Saha Cardiovascular Research Center Faculty Publications
OBJECTIVE: Ghrelin, a stomach-derived, secreted peptide, and its receptor (growth hormone secretagogue receptor, GHSR) are known to modulate food intake and energy homeostasis. The ghrelin system is also expressed broadly in cardiovascular tissues. Since ghrelin has been associated with anti-inflammatory and anti-atherogenic properties, but is also well known to promote obesity and impair glucose metabolism, we investigated whether ghrelin has any impact on the development of atherosclerosis. The hypothesis that endogenous ghrelin signaling may be involved in atherosclerosis has not been tested previously.
METHODS AND RESULTS: We crossed ghrelin receptor knockout mice (GHSr-/-) into a low-density lipoprotein receptor-null …
Manganese Superoxide Dismutase: Guardian Of The Powerhouse, Aaron K. Holley, Vasudevan Bakthavatchalu, Joyce M. Velez-Roman, Daret K. St. Clair
Manganese Superoxide Dismutase: Guardian Of The Powerhouse, Aaron K. Holley, Vasudevan Bakthavatchalu, Joyce M. Velez-Roman, Daret K. St. Clair
Toxicology and Cancer Biology Faculty Publications
The mitochondrion is vital for many metabolic pathways in the cell, contributing all or important constituent enzymes for diverse functions such as β-oxidation of fatty acids, the urea cycle, the citric acid cycle, and ATP synthesis. The mitochondrion is also a major site of reactive oxygen species (ROS) production in the cell. Aberrant production of mitochondrial ROS can have dramatic effects on cellular function, in part, due to oxidative modification of key metabolic proteins localized in the mitochondrion. The cell is equipped with myriad antioxidant enzyme systems to combat deleterious ROS production in mitochondria, with the mitochondrial antioxidant enzyme manganese …
Epithelial Interleukin-8 Responses To Oral Bacterial Biofilms, Rebecca Peyyala, Sreenatha S. Kirakodu, Lucia Novakova, Jeffrey L. Ebersole
Epithelial Interleukin-8 Responses To Oral Bacterial Biofilms, Rebecca Peyyala, Sreenatha S. Kirakodu, Lucia Novakova, Jeffrey L. Ebersole
Center for Oral Health Research Faculty Publications
An in vitro model of bacterial biofilms on rigid gas-permeable contact lenses (RGPLs) was developed to challenge oral epithelial cells. This novel model provided seminal data on oral biofilm-host cell interactions, and with selected bacteria, the biofilms were more effective than their planktonic counterparts at stimulating host cell responses.
Sr-A Ligand And M-Csf Dynamically Regulate Sr-A Expression And Function In Primary Macrophages Via P38 Mapk Activation, Dejan Nikolic, Lindsay Calderon, Liqin Du, Steven R. Post
Sr-A Ligand And M-Csf Dynamically Regulate Sr-A Expression And Function In Primary Macrophages Via P38 Mapk Activation, Dejan Nikolic, Lindsay Calderon, Liqin Du, Steven R. Post
Pharmacology and Nutritional Sciences Faculty Publications
BACKGROUND: Inflammation is characterized by dynamic changes in the expression of cytokines, such as M-CSF, and modifications of lipids and proteins that result in the formation of ligands for Class A Scavenger Receptors (SR-A). These changes are associated with altered SR-A expression in macrophages; however, the intracellular signal pathways involved and the extent to which SR-A ligands regulate SR-A expression are not well defined. To address these questions, SR-A expression and function were examined in resident mouse peritoneal macrophages incubated with M-CSF or the selective SR-A ligand acetylated-LDL (AcLDL).
RESULTS: M-CSF increased SR-A expression and function, and required the specific …
Role Of Phosphoinositide 3-Kinase – Akt Signaling Pathway In The Age-Related Cytokine Dysregulation In Splenic Macrophages Stimulated Via Tlr-2 Or Tlr-4 Receptors, Mosoka Papa Fallah, R. Lakshman Chelvarajan, Beth A. Garvy, Subbarao Bondada
Role Of Phosphoinositide 3-Kinase – Akt Signaling Pathway In The Age-Related Cytokine Dysregulation In Splenic Macrophages Stimulated Via Tlr-2 Or Tlr-4 Receptors, Mosoka Papa Fallah, R. Lakshman Chelvarajan, Beth A. Garvy, Subbarao Bondada
Microbiology, Immunology, and Molecular Genetics Faculty Publications
Age-associated defects in both B-lymphocytes and macrophages in elderly result in a reduction in the efficacy of vaccines to many Gram positive bacteria like Streptococcus pneumoniae. Splenic macrophages from aged mice have been shown to have a defect in production of pro-inflammatory cytokines (IL-6, IL-12, IL-1β, TNF-α) but exhibit increased production of IL-10 upon TLR4 ligation. Here we showed that aged macrophages demonstrate similar cytokine dysregulation phenotype upon stimulation with TLR2 ligands, or killed S. pneumoniae. We hypothesized that an age-associated increase in activity of phosphatidyl inositol 3-kinase (PI3K)-Akt signaling pathway may be playing a causal role in …
Recombination Phenotypes Of The Nci-60 Collection Of Human Cancer Cells, Dawn M. Stults, Michael W. Killen, Brent J. Shelton, Andrew J. Pierce
Recombination Phenotypes Of The Nci-60 Collection Of Human Cancer Cells, Dawn M. Stults, Michael W. Killen, Brent J. Shelton, Andrew J. Pierce
Microbiology, Immunology, and Molecular Genetics Faculty Publications
BACKGROUND: The NCI-60 is a collection of tumor cell lines derived from a variety of human adult cancer tissue types and is commonly used for genetic analysis and screening of potential chemotherapeutic agents. We wanted to understand the contributions of specific mechanisms of genomic instability to the etiology of cancers represented by the NCI-60.
RESULTS: We screened the NCI-60 for dysregulated homologous recombination by using the gene cluster instability (GCI) assay we pioneered, and for defects in base excision repair by sensitivity to 5-hydroxymethyl-2'-deoxyuridine (hmdUrd). We identified subsets of the NCI-60 lines that either displayed the characteristic molecular signature of …
Oxidative Stress Accumulates In Adipose Tissue During Aging And Inhibits Adipogenesis, Hannes M. Findeisen, Kevin J. Pearson, Florence Gizard, Yue Zhao, Hua Qing, Karrie L Jones, Dianne Cohn, Elizabeth B. Heywood, Rafael De Cabo, Dennis Bruemmer
Oxidative Stress Accumulates In Adipose Tissue During Aging And Inhibits Adipogenesis, Hannes M. Findeisen, Kevin J. Pearson, Florence Gizard, Yue Zhao, Hua Qing, Karrie L Jones, Dianne Cohn, Elizabeth B. Heywood, Rafael De Cabo, Dennis Bruemmer
Saha Cardiovascular Research Center Faculty Publications
Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at …
Phenethyl Isothiocyanate Exhibits Antileukemic Activity In Vitro And In Vivo By Inactivation Of Akt And Activation Of Jnk Pathways, N. Gao, Amit Budhraja, S. Cheng, E.-H. Liu, J. Chen, Z. Yang, D. Chen, Zhuo Zhang, Xianglin Shi
Phenethyl Isothiocyanate Exhibits Antileukemic Activity In Vitro And In Vivo By Inactivation Of Akt And Activation Of Jnk Pathways, N. Gao, Amit Budhraja, S. Cheng, E.-H. Liu, J. Chen, Z. Yang, D. Chen, Zhuo Zhang, Xianglin Shi
Toxicology and Cancer Biology Faculty Publications
Effects of phenethyl isothiocyanate (PEITC) have been investigated in human leukemia cells (U937, Jurkat, and HL-60) as well as in primary human acute myeloid leukemia (AML) cells in relation to apoptosis and cell signaling events. Exposure of cells to PEITC resulted in pronounced increase in the activation of caspase-3, -8, -9, cleavage/degradation of PARP, and apoptosis in dose- and time-dependent manners. These events were accompanied by the caspase-independent downregulation of Mcl-1, inactivation of Akt, as well as activation of Jun N-terminal kinase (JNK). Inhibition of PI3K/Akt by LY294002 significantly enhanced PEITC-induced apoptosis. Conversely, enforced activation of Akt by a constitutively …
Nanotubes As Mitochondrial Uncouplers, Patrick G. Sullivan
Nanotubes As Mitochondrial Uncouplers, Patrick G. Sullivan
Neuroscience Faculty Patents
A method of uncoupling mitochondria in a subject including administering nanotubes to the subject in a therapeutically effective amount, wherein the nanotubes are self-rectifying is provided. A method of decreasing reactive oxygen species and decreasing detrimental loading of Ca2+ into mitochondria is provided, including administering a pharmaceutically effective amount of nanotubes into the subject. A method of reducing weight, treating cancer, reducing the effects of traumatic brain injury, or reducing the effects of ageing, in a subject including administering a pharmaceutically effective amount of nanotubes into the subject is also provided.
P53 Regulates Oxidative Stress-Mediated Retrograde Signaling: A Novel Mechanism For Chemotherapy-Induced Cardiac Injury, Joyce M. Velez, Sumitra Miriyala, Ramaneeya Nithipongvanitch, Teresa Noel, Chotiros D. Plabplueng, Terry Oberley, Paiboon Jungsuwadee, Holly Van Remmen, Mary Vore, Daret K. St Clair
P53 Regulates Oxidative Stress-Mediated Retrograde Signaling: A Novel Mechanism For Chemotherapy-Induced Cardiac Injury, Joyce M. Velez, Sumitra Miriyala, Ramaneeya Nithipongvanitch, Teresa Noel, Chotiros D. Plabplueng, Terry Oberley, Paiboon Jungsuwadee, Holly Van Remmen, Mary Vore, Daret K. St Clair
Toxicology and Cancer Biology Faculty Publications
The side effects of cancer therapy on normal tissues limit the success of therapy. Generation of reactive oxygen species (ROS) has been implicated for numerous chemotherapeutic agents including doxorubicin (DOX), a potent cancer chemotherapeutic drug. The production of ROS by DOX has been linked to DNA damage, nuclear translocation of p53, and mitochondrial injury; however, the causal relationship and molecular mechanisms underlying these events are unknown. The present study used wild-type (WT) and p53 homozygous knock-out (p53(-/-)) mice to investigate the role of p53 in the crosstalk between mitochondria and nucleus. Injecting mice with DOX (20 mg/kg) causes oxidative stress …
In Vitro Amplification Of Misfolded Prion Protein Using Lysate Of Cultured Cells, Charles E. Mays, Jihyun Yeom, Hae-Eun Kang, Jifeng Bian, Vadim Khaychuk, Younghwan Kim, Jason C Bartz, Glenn C Telling, Chongsuk Ryou
In Vitro Amplification Of Misfolded Prion Protein Using Lysate Of Cultured Cells, Charles E. Mays, Jihyun Yeom, Hae-Eun Kang, Jifeng Bian, Vadim Khaychuk, Younghwan Kim, Jason C Bartz, Glenn C Telling, Chongsuk Ryou
Microbiology, Immunology, and Molecular Genetics Faculty Publications
Protein misfolding cyclic amplification (PMCA) recapitulates the prion protein (PrP) conversion process under cell-free conditions. PMCA was initially established with brain material and then with further simplified constituents such as partially purified and recombinant PrP. However, availability of brain material from some species or brain material from animals with certain mutations or polymorphisms within the PrP gene is often limited. Moreover, preparation of native PrP from mammalian cells and tissues, as well as recombinant PrP from bacterial cells, involves time-consuming purification steps. To establish a convenient and versatile PMCA procedure unrestricted to the availability of substrate sources, we attempted to …
The Role Of Xpg In Processing (Cag)N/(Ctg)N Dna Hairpins, Caixia Hou, Tianyi Zhang, Lei Tian, Jian Huang, Liya Gu, Guo-Min Li
The Role Of Xpg In Processing (Cag)N/(Ctg)N Dna Hairpins, Caixia Hou, Tianyi Zhang, Lei Tian, Jian Huang, Liya Gu, Guo-Min Li
Toxicology and Cancer Biology Faculty Publications
BACKGROUND: During DNA replication or repair, disease-associated (CAG)n/(CTG)n expansion can result from formation of hairpin structures in the repeat tract of the newly synthesized or nicked DNA strand. Recent studies identified a nick-directed (CAG)n/(CTG)n hairpin repair (HPR) system that removes (CAG)n/(CTG)n hairpins from human cells via endonucleolytic incisions. Because the process is highly similar to the mechanism by which XPG and XPF endonucleases remove bulky DNA lesions during nucleotide excision repair, we assessed the potential role of XPG in conducting (CAG)n/(CTG)n HPR.
RESULTS: To determine if the XPG endonuclease is involved in (CAG)n/(CTG)n hairpin removal, two XPG-deficient cell lines (GM16024 …
Patterns Of Microrna Expression In Normal And Early Alzheimer's Disease Human Temporal Cortex: White Matter Versus Gray Matter, Wang-Xia Wang, Qingwei Huang, Yanling Hu, Arnold J. Stromberg, Peter T. Nelson
Patterns Of Microrna Expression In Normal And Early Alzheimer's Disease Human Temporal Cortex: White Matter Versus Gray Matter, Wang-Xia Wang, Qingwei Huang, Yanling Hu, Arnold J. Stromberg, Peter T. Nelson
Pathology and Laboratory Medicine Faculty Publications
MicroRNA (miRNA) expression was assessed in human cerebral cortical gray matter (GM) and white matter (WM) in order to provide the first insights into the difference between GM and WM miRNA repertoires across a range of Alzheimer's disease (AD) pathology. RNA was isolated separately from GM and WM portions of superior and middle temporal cerebral cortex (N = 10 elderly females, postmortem interval < 4 h). miRNA profiling experiments were performed using state-of-the-art Exiqon© LNA-microarrays. A subset of miRNAs that appeared to be strongly expressed according to the microarrays did not appear to be conventional miRNAs according to Northern blot analyses. Some well-characterized miRNAs were substantially enriched in WM …
The Differential Effect Of Toxoplasma Gondii Infection On The Stability Of Bcl2-Family Members Involves Multiple Activities, John Cherrington Carmen, Anthony Peter Sinai
The Differential Effect Of Toxoplasma Gondii Infection On The Stability Of Bcl2-Family Members Involves Multiple Activities, John Cherrington Carmen, Anthony Peter Sinai
Microbiology, Immunology, and Molecular Genetics Faculty Publications
The regulation of mitochondrial permeability, a key event in the initiation of apoptosis is governed by the opposing actions of the pro- and anti-apoptotic members of the BCL2-family of proteins. The BCL2-family can be classified further based on the number of BCL-homology (BH) domains they encode. Pathogen mediated modulation of BCL2-family members play a significant role in their ability to affect the apoptotic pathways in the infected host cell. The protozoan parasite Toxoplasma gondii establishes a profound blockade of apoptosis noted by a requirement for host NFκB activity and correlating with the selective degradation of pro-apoptotic BCL2-family members. In this …
Role Of Angiotensin Converting Enzyme 2 (Ace2) In Obesity-Associated Hypertension, Manisha Gupte
Role Of Angiotensin Converting Enzyme 2 (Ace2) In Obesity-Associated Hypertension, Manisha Gupte
University of Kentucky Doctoral Dissertations
The purpose of this research was to determine whether adipocytes express ACE2 and its role in obesity-associated hypertension with diet-induced obesity.
To determine if ACE2 was expressed in adipose tissue and its regulation in the setting of diet-induced obesity, we fed male mice either a low fat (LF) or high fat (HF) diet acutely (1 week) or chronically ( 4 months). We demonstrated that ACE2 was regulated specifically in adipose tissue with consumption of a HF diet. However, with chronic HF feeding adipose ACE2 was dysregulated resulting in activation of the systemic RAS and increased blood pressure.
To determine the …
Genotoxin-Induced Acetylation Of The Werner Syndrome Protein (Wrn) And Effect On Its Dna Metabolic Function, Enerlyn Meliza Lozada Santiago
Genotoxin-Induced Acetylation Of The Werner Syndrome Protein (Wrn) And Effect On Its Dna Metabolic Function, Enerlyn Meliza Lozada Santiago
University of Kentucky Doctoral Dissertations
Loss of function of the WRN protein causes the genetic disorder Werner Syndrome that is characterized by increased cancer and premature aging. WRN belongs to the RecQ helicase family that plays key roles in preventing genome instability. In response to treatment with genotoxins, WRN is subject to post-translational modification. The relationship of post-translational modification of WRN with its function in DNA metabolism is unknown. There is accumulating evidence suggesting that WRN contributes to the maintenance of genomic integrity through its involvement in DNA replication. Consistent with this notion, WS cells are sensitive to DNA replication inhibitors and DNA damaging agents …
Identification Of Activities Involved In Cag/Ctg Repeat Instability, Nelson Lap Shun Chan
Identification Of Activities Involved In Cag/Ctg Repeat Instability, Nelson Lap Shun Chan
University of Kentucky Doctoral Dissertations
CAG/CTG repeat instability is associated with at least 14 neurological disorders, including Huntington’s disease and Myotonic dystrophy type 1. In vitro and in vivo studies have showed that CAG/CTG repeats form a stable hairpin that is believed to be the intermediate for repeat expansion and contraction.
Addition of extra DNA is essential for repeat expansion, so DNA synthesis is one of the keys for repeat expansion. In vivo studies reveal that 3’ CTG slippage with subsequent hairpin formation (henceforth called the 3’ CTG slippage hairpin) occurs during DNA synthesis. It is proposed that hairpin tolerance machinery is activated because prolonged …
Post-Transcriptional Regulation Of Afp And Igm Genes, Lilia M. Turcios
Post-Transcriptional Regulation Of Afp And Igm Genes, Lilia M. Turcios
University of Kentucky Doctoral Dissertations
Gene expression can be regulated at multiple steps once transcription is initiated. I have studied two different gene models, the α-Fetoprotein (AFP) and the immunoglobulin heavy chain (IgM) genes, to better understand post-transcriptional gene regulation mechanisms. The AFP gene is highly expressed during fetal liver development and dramatically repressed after birth. There is a mouse strain-specific difference between adult levels of AFP, with BALB/cJ mice expressing 10 to 20-fold higher levels compared to other mouse strains. BALB/cJ mice express low levels of Zhx2 and thus incompletely repress AFP. Despite differences in steady state AFP mRNA levels in the adult liver …
Computational Analyses Of The Uptake And Distribution Of Carbon Monoxide (Co) In Human Subjects, Kinnera Chada
Computational Analyses Of The Uptake And Distribution Of Carbon Monoxide (Co) In Human Subjects, Kinnera Chada
University of Kentucky Doctoral Dissertations
Carbon monoxide (CO) is an odorless, colorless, tasteless gas that binds to hemoglobin with high affinity. This property underlies the use of low doses of CO to determine hemoglobin mass (MHb) in the fields of clinical and sports medicine. However, hemoglobin bound to CO is unable to transport oxygen and exposure to high CO concentrations is a significant environmental and occupational health concern. These contrasting aspects of CO—clinically useful in low doses but potentially lethal in higher doses—mandates a need for a quantitative understanding of the temporal profiles of the uptake and distribution of CO …
Novel Mechanisms In Inflammatory Bowel Disease, Razvan I. Arsenescu
Novel Mechanisms In Inflammatory Bowel Disease, Razvan I. Arsenescu
University of Kentucky Doctoral Dissertations
Inflammatory Bowel Diseases, Crohn's Disease and Ulcerative colitis, are idiopathic chronic conditions with multifactorial determinants. In general, terms, intestinal inflammation results from abnormal host-microbe interactions. Alterations in homeostasis involve host genetic factors, environmental cues and unique luminal microbial niches. We have examined the coordinated expressions of several molecular targets relevant to the mucosal immune system and identified signature biomarkers of IBD. Qualitative and quantitative changes in the composition of microbiota can be related to unique immuno-phenotypes. This in turn can have more systemic effects that involve energy metabolism. Adiponectin, an adipose tissue derived adipokine, can restore cellular ATP levels and …
Androgen Increases Angiotensin Receptor Type 1a On Smooth Muscle Cells To Promote Angiotensin Ii-Induced Abdominal Aortic Aneurysms, Xuan Zhang
University of Kentucky Doctoral Dissertations
The purpose of this study was to determine whether androgen promotes AT1aR expression on smooth muscle to confer high prevalence of AngII-induced AAAs in hyperlipidemic mice. In addition, we also investigate the role of androgen in the progression of established AngII-induced AAAs.
First, we sought to examine the role of endogenous androgen in the growth of established AngII-induced AAAs. By castrating male mice, we demonstrated that removal of endogenous androgen significantly decreased the progressive lumen dilation of established AngII-induced AAAs in male ApoE-/- mice, but had no effect on external AAA diameters. These results suggest that androgen contributes to the …
Genome-Wide Association Studies At The Interface Of Alzheimer’S Disease And Epidemiologically Related Disorders, Christopher Ryan Simmons
Genome-Wide Association Studies At The Interface Of Alzheimer’S Disease And Epidemiologically Related Disorders, Christopher Ryan Simmons
University of Kentucky Doctoral Dissertations
Genome-wide association studies (GWAS)s provide an unbiased means of exploring the landscape of complex genetic disease. As such, these studies have identified genetic variants that are robustly associated with a multitude of conditions. I hypothesize that these genetic variants serve as excellent tools for evaluation of the genetic interface between epidemiologically related conditions. Herein, I test the association between SNPs associated with either (i) plasma lipids, (ii) rheumatoid arthritis (RA) or (iii) diabetes mellitus (DM) and late-onset Alzheimer’s disease (AD) to identify shared genetic variants. Regarding the most significantly AD-associated variants, I have also attempted to elucidate their molecular function. …
Tonic Inhibition Of Chronic Pain By Neuropeptide Y, Brian Solway, Soma C. Bose, Gregory Corder, Renee R. Donahue, Bradley K. Taylor
Tonic Inhibition Of Chronic Pain By Neuropeptide Y, Brian Solway, Soma C. Bose, Gregory Corder, Renee R. Donahue, Bradley K. Taylor
Renee R. Donahue
Dramatically up-regulated in the dorsal horn of the mammalian spinal cord following inflammation or nerve injury, neuropeptide Y (NPY) is poised to regulate the transmission of sensory signals. We found that doxycycline-induced conditional in vivo (Npytet/tet) knockdown of NPY produced rapid, reversible, and repeatable increases in the intensity and duration of tactile and thermal hypersensitivity. Remarkably, when allowed to resolve for several weeks, behavioral hypersensitivity could be dramatically reinstated with NPY knockdown or intrathecal administration of Y1 or Y2 receptor antagonists. In addition, Y2 antagonism increased dorsal horn expression of Fos and phosphorylated form of extracellular signal-related kinase. Taken together, …
Traumatic Brain Injury: Cyclophilin D As A Therapeutic Target And The Neuropathology Caused By Blast, Ryan Douglas Readnower
Traumatic Brain Injury: Cyclophilin D As A Therapeutic Target And The Neuropathology Caused By Blast, Ryan Douglas Readnower
University of Kentucky Doctoral Dissertations
With an estimated incidence of 1.5 million each year, traumatic brain injury (TBI) is a major cause of mortality and morbidity in the United States. Opening of the mitochondrial permeability transition pore (mPTP) is a key event contributing to TBI pathology. Cyclophilin D (CypD), a matrix peptidyl-prolyl cis-trans isomerase, is believed to be the regulating component of the mPTP. Cyclosporin A, an immunosuppressant drug, inhibits CypD and blocks mPTP formation and has been shown to be neuroprotective following TBI. However, it is unclear if CsA’s neuroprotective mechanism is due to inhibition of CypD and/or immuno-suppression. Therefore to directly assess the …
Lysophosphatidic Acid Production And Signaling In Platelets, Zachary Bennett Fulkerson
Lysophosphatidic Acid Production And Signaling In Platelets, Zachary Bennett Fulkerson
Theses and Dissertations--Physiology
Lysophosphatidic acid (LPA) belongs to a class of extracellular lipid signaling molecules. In the vasculature, LPA may regulate platelet activation and modulate endothelial and smooth muscle cell function. LPA has therefore been proposed as a mediator of cardiovascular disease.
The bulk of circulating LPA is produced from plasma lysophosphatidylcholine (LPC) by autotaxin (ATX), a secreted lysophospholipase D (lysoPLD). Early studies suggest that some of the production of circulating LPA is platelet-dependent. ATX possesses an N-terminal somatomedin B-like domain suggesting the hypothesis that ATX interacts with platelet integrins which may localize ATX to substrate in the membrane and/or alter the catalytic …
Trichloroethylene Exposure And Traumatic Brain Injury Interact And Produce Dual Injury Based Pathology And Pioglitazone Can Attenuate Deficits Following Traumatic Brain Injury, Andrew David Sauerbeck
Trichloroethylene Exposure And Traumatic Brain Injury Interact And Produce Dual Injury Based Pathology And Pioglitazone Can Attenuate Deficits Following Traumatic Brain Injury, Andrew David Sauerbeck
University of Kentucky Doctoral Dissertations
The development of Parkinson's disease (PD) in humans has been linked to genetic and environmental factors for many years. However, finding common single insults which can produce pathology in humans has proved difficult. Exposure to trichloroethylene (TCE) or traumatic brain injury (TBI) has been shown to be linked to PD and it has also been proposed that multiple insults may be needed for disease development.
The present studies show that exposure to TCE prior to a TBI can result in pathology similar to early PD and that the interaction of both insults is required for impairment in behavioral function, and …
The Role Of The Nr4a Orphan Nuclear Receptor Nor1 In Vascular Cells And Atherosclerosis, Yue Zhao
The Role Of The Nr4a Orphan Nuclear Receptor Nor1 In Vascular Cells And Atherosclerosis, Yue Zhao
University of Kentucky Doctoral Dissertations
The neuron-derived orphan receptor 1 (NOR1) belongs to the NR4A nuclear receptor subfamily. As an immediate early response gene, NOR1 is rapidly induced by a broad spectrum of physiological and pathological signals. Functional studies demonstrate NOR1 as a constitutively active ligand-independent nuclear receptor whose transcriptional activity is dependent on both expression level and posttranslational modifications. To date, an increasing number of studies have demonstrated a pivotal role of NOR1 in the transcriptional control of metabolism and the development of cardiovascular diseases.
In this dissertation, we demonstrate NOR1 expression in endothelial cells and sub-endothelial cells of human atherosclerotic lesions. In response …