Physiology Commons^™

Estrogen Receptor Alpha (Esr1)-Dependent Regulation Of The Mouse Oviductal Transcriptome, Katheryn L. Cerny, Rosanne A. C. Ribeiro, Myoungkun Jeoung, Chemyong Ko, Phillip J. Bridges

Animal and Food Sciences Faculty Publications

Estrogen receptor-α (ESR1) is an important transcriptional regulator in the mammalian oviduct, however ESR1-dependent regulation of the transcriptome of this organ is not well defined, especially at the genomic level. The objective of this study was therefore to investigate estradiol- and ESR1-dependent regulation of the transcriptome of the oviduct using transgenic mice, both with (ESR1KO) and without (wild-type, WT) a global deletion of ESR1. Oviducts were collected from ESR1KO and WT littermates at 23 days of age, or ESR1KO and WT mice were treated with 5 IU PMSG to stimulate follicular development and the production of ovarian estradiol, and the …

Serum Amyloid A Impairs The Antiinflammatory Properties Of Hdl, Chang Yeop Han, Chongren Tang, Myriam E. Guevara, Hao Wei, Tomasz Wietecha, Baohai Shao, Savitha Subramanian, Mohamed Omer, Shari Wang, Kevin D. O'Brien, Santica M. Marcovina, Thomas N. Wight, Tomas Vaisar, Maria C. De Beer, Frederick C. De Beer, William R. Osborne, Keith B. Elkon, Alan Chait

Physiology Faculty Publications

HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO₃ fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO₃-injected mice lacking Saa1.1 …

Rfx Transcription Factors Are Essential For Hearing In Mice, Ran Elkon, Beatrice Milon, Laura Morrison, Manan Shah, Sarath Vijayakumar, Manoj Racherla, Carmen C. Leitch, Lorna Silipino, Shadan Hadi, Michèle Weiss-Gayet, Emmanuèle Barras, Christoph D. Schmid, Aouatef Ait-Lounis, Ashley Barnes, Yang Song, David J. Eisenman, Efrat Eliyahu, Gregory I. Frolenkov, Scott E. Strome, Bénédicte Durand, Norann A. Zaghloul, Sherri M. Jones, Walter Reith, Ronna Hertzano

Physiology Faculty Publications

Sensorineural hearing loss is a common and currently irreversible disorder, because mammalian hair cells (HCs) do not regenerate and current stem cell and gene delivery protocols result only in immature HC-like cells. Importantly, although the transcriptional regulators of embryonic HC development have been described, little is known about the postnatal regulators of maturating HCs. Here we apply a cell type-specific functional genomic analysis to the transcriptomes of auditory and vestibular sensory epithelia from early postnatal mice. We identify RFX transcription factors as essential and evolutionarily conserved regulators of the HC-specific transcriptomes, and detect Rfx1,2,3,5 and 7 in the developing HCs. …

Macrophage Migration Inhibitory Factor Mediates Par-Induced Bladder Pain., Dimitrios E. Kouzoukas, Katherine L. Meyer-Siegler, Fei Ma, Karin N. Westlund, David E. Hunt, Pedro L. Vera

Physiology Faculty Publications

INTRODUCTION: Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is constitutively expressed in urothelial cells that also express protease-activated receptors (PAR). Urothelial PAR1 receptors were shown to mediate bladder inflammation. We showed that PAR1 and PAR4 activator, thrombin, also mediates urothelial MIF release. We hypothesized that stimulation of urothelial PAR1 or PAR4 receptors elicits release of urothelial MIF that acts on MIF receptors in the urothelium to mediate bladder inflammation and pain. Thus, we examined the effect of activation of specific bladder PAR receptors on MIF release, bladder pain, micturition and histological changes.

METHODS: MIF release was measured …

Enhanced Nmda Receptor-Mediated Modulation Of Excitatory Neurotransmission In The Dorsal Vagal Complex Of Streptozotocin-Treated, Chronically Hyperglycemic Mice, Eva C. Bach, Katalin Cs. Halmos, Bret N. Smith

Physiology Faculty Publications

A variety of metabolic disorders, including complications experienced by diabetic patients, have been linked to altered neural activity in the dorsal vagal complex. This study tested the hypothesis that augmentation of N-Methyl-D-Aspartate (NMDA) receptor-mediated responses in the vagal complex contributes to increased glutamate release in the dorsal motor nucleus of the vagus nerve (DMV) in mice with streptozotocin-induced chronic hyperglycemia (i.e., hyperglycemic mice), a model of type 1 diabetes. Antagonism of NMDA receptors with AP-5 (100 μM) suppressed sEPSC frequency in vagal motor neurons recorded in vitro, confirming that constitutively active NMDA receptors regulate glutamate release in the DMV. There …

The Biology Of Claudin 6 (Cldn6) In The Developing Mouse Lung, Felix Ruben Jimenez Rondan

Theses and Dissertations

The tight junctions (TJ), which are located in the apical region between epithelial and endothelial cells, regulate the paracellular diffusion of ions and small molecules and play an important role in maintaining cell polarity, cell-cell integrity, and permeability. In the lung, epithelial cells are attached by TJ structures. They provide a permeable barrier and cell communication. The loss of barrier integrity, which is maintained by the expression of claudins (Cldn), results in cellular permibilization and leads to paracellular diffusion of solutes and harmful molecules. There are 27 known Cldn homologous members in mice and human. Cldn6 is mostly expressed in …

Smooth-Muscle Bmal1 Participates In Blood Pressure Circadian Rhythm Regulation, Zhongwen Xie, Wen Su, Shu Liu, Guogang Zhao, Karyn Esser, Elizabeth A. Schroder, Mellani Lefta, Harald M. Stauss, Zhenheng Guo, Ming Cui Gong

Physiology Faculty Publications

As the central pacemaker, the suprachiasmatic nucleus (SCN) has long been considered the primary regulator of blood pressure circadian rhythm; however, this dogma has been challenged by the discovery that each of the clock genes present in the SCN is also expressed and functions in peripheral tissues. The involvement and contribution of these peripheral clock genes in the circadian rhythm of blood pressure remains uncertain. Here, we demonstrate that selective deletion of the circadian clock transcriptional activator aryl hydrocarbon receptor nuclear translocator-like (Bmal1) from smooth muscle, but not from cardiomyocytes, compromised blood pressure circadian rhythm and decreased blood …

Neutral Sphingomyelinase-3 Mediates Tnf-Stimulated Oxidant Activity In Skeletal Muscle, Jennifer S. Moylan, Jeffrey D. Smith, Erin M. Wolf Horrell, Julie B. Mclean, Gergana M. Deevska, Mark R. Bonnell, Mariana N. Nikolova‑Karakashian, Michael B. Reid

Physiology Faculty Publications

AIMS: Sphingolipid and oxidant signaling affect glucose uptake, atrophy, and force production of skeletal muscle similarly and both are stimulated by tumor necrosis factor (TNF), suggesting a connection between systems. Sphingolipid signaling is initiated by neutral sphingomyelinase (nSMase), a family of agonist-activated effector enzymes. Northern blot analyses suggest that nSMase3 may be a striated muscle-specific nSMase. The present study tested the hypothesis that nSMase3 protein is expressed in skeletal muscle and functions to regulate TNF-stimulated oxidant production.

RESULTS: We demonstrate constitutive nSMase activity in skeletal muscles of healthy mice and humans and in differentiated C2C12 myotubes. nSMase3 ( …

Vitamin A Deficiency Causes Ovulation Abnormalities In Mice, Rebecca Ursin

DePaul Discoveries

Retinoic acid (RA) is an active metabolite of vitamin A (VA) and is involved in tissue organization, patterning, and growth. RA has been shown to regulate male reproduction, however information on its role in ovary development is limited. To investigate the functions of RA in the ovary, we examined its role in ovary development and ovulation using an in vivo dietary VA-deprivation animal model. Our preliminary results have shown that VA deficiency causes a variety of ovarian pathologies, including reduced numbers of total follicles and corpus lutea, formation of hemorrhagic and atretic follicles, and formation of bursa and follicular cysts. …

Arrhythmogenic Calmodulin Mutations Disrupt Intracellular Cardiomyocyte Ca2+ Regulation By Distinct Mechanisms, Guo Yin, Faisal Hassan, Ayman R. Haroun, Lisa L. Murphy, Lia Crotti, Peter J. Schwartz, Alfred L. George, Jonathan Satin

Physiology Faculty Publications

BACKGROUND: Calmodulin (CaM) mutations have been identified recently in subjects with congenital long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT), but the mechanisms responsible for these divergent arrhythmia-susceptibility syndromes in this context are unknown. We tested the hypothesis that LQTS-associated CaM mutants disrupt Ca²⁺ homeostasis in developing cardiomyocytes possibly by affecting either late Na current or Ca²⁺-dependent inactivation of L-type Ca²⁺ current.

METHODS AND RESULTS: We coexpressed CaM mutants with the human cardiac Na channel (Na_V1.5) in tsA201 cells, and we used mammalian fetal ventricular cardiomyocytes to investigate LQTS- and CPVT-associated CaM …

Expression Of Osteoarthritis Biomarkers In Temporomandibular Joints Of Mice With And Without Receptor For Advanced Glycation End Products (Rage), Elizabeth Murayama Chavez Matias

Theses and Dissertations

This thesis will be organized into three chapters discussing the mechanism underlying the onset and progression of osteoarthritis (OA) in the temporomandibular joint (TMJ). Understanding the mechanism of OA development in the TMJ helps in understanding how OA progresses and how to treat this disease. The goal of this investigation is to examine the process of cartilage degeneration and OA biomarker expression in the TMJ to understand their role in TMJ OA onset and development.Chapter one covers mechanisms that are altered in TMJ OA during disease progression. Using animal models with different stressors such as mechanical disturbances, direct injury, and …

Researching The Effects Of Osteoarthritis As A Systemic Immune Response, Danielle Peterson, Dr. David Kooyman

Journal of Undergraduate Research

Our bodies are dynamic structures that do not operate as individual compartments, but as a whole. When something goes awry in one specific tissue or organ, specific signals from that diseased area are released affect other tissues. I received an ORCA grant last year to study my hypothesis that degradation of Osteoarthritis (OA) is primarily associated with a systemic immune response to trauma of articular cartilage. In order to verify this hypothesis, a treatment that creates OA in one localized area while other tissues remained undamaged was needed. The OA genetic mutant mice that researchers normally turn to couldn’t be …

Degeneration Of Articular Cartilage In The Temporomandibluar Joint Of Mice With Disproportionate Micromelia (Dmm), Robert R. Seegmiller

Journal of Undergraduate Research

Osteoarthritis is a common degenerative joint disease affecting humans today. This disease leads to premature degradation of articular cartilage in joints, such as the knee, and it can be caused by mutations in collagen coding genes. Collagen is the basic building block of cartilage, so any mutations would affect the response of collagen to outside factors.

Type Iia Procollagen – Osteoarthritis Biomarker In Dmm Mice, John Mcallister, Kenneth Merrell, Dr. Robert E. Seegmiller

Journal of Undergraduate Research

Arthritis is a painful, debilitating disease that affects sixty-six million Americans (The Arthritis Foundation 2005). Osteoarthritis (OA), results in joint degeneration caused by cartilage erosion and synovial inflammation. While the causes of OA remain unclear, current evidence suggests that both mechanical and biochemical factors can initiate OA. Ethical and practical issues limiting the availability of human tissue in OA research necessitate the use of animal models. Mice with the disproportionate micromelia mutation (Dmm) exhibit histological characteristics similar to those of humans with OA. Use of Dmm as a model of OA may lead a discovery of a common mechanism associated …

Retinal Detachment In Mice With Disproportionate Micromelia, Jared R. Jackson, Dr. Robert Seegmiller

Journal of Undergraduate Research

Stickler syndrome, caused by a mutation of the Collagen 2A1 gene, is the most common cause of inherited retinal detachment in children. A mutation of the same gene in mice causes Disproportionate Micromelia (Dmm). “In cases where mouse mutations occur in genes that are also responsible for human disorders, the mouse strains provide essential model systems for studies of pathogenetic mechanisms.” The purpose of this study is to find and document evidence of retinal detachment that is hypothesized in heterozygous (Dmm/+) mutant mice.

The Role Of Wnt Ligands In The Development Of Limb Musculature, Jordan Huber, Dr. Jeffery Barrow

Journal of Undergraduate Research

The Wnt family of secreted proteins consists of 19 family members (in the mouse) and is known to signal through multiple pathways that regulate crucial processes in the development of almost all tissues. Dissecting the roles of individual Wnts has been hampered due to functional redundancy that exists between family members. By making a conditional allele of the O-acyltransferase, Porcupine (Porcn), that is required for the secretion of all Wnt ligands, and a tissue specific enhancer to drive Cre expression, we are able to eliminate the secretion of all Wnt ligands in tissues of interest. We eliminated the secretion of …

Effects Of Tlr-4 Blockers On The Severity Of Oa In Rage Knockout Mice, Jeffrey Kartchner, Dr. David Kooyman

Journal of Undergraduate Research

As the population in the US continues to age, osteoarthritis (OA) is becoming a larger issue, currently effecting over 27 million people1. Presently, pharmaceutical options aim to lessen the effects of the disease, while no preventative treatment is currently available. Much of the current arthritis research is targeted at the effects of inflammation on the progression of OA. Our lab has shown in previous research that mice lacking the Receptor for Advanced Glycation End Products (RAGE) are protected from OA2. Other labs have shown the possibility of Toll-like receptor 4 (TLR-4) involvement in the progression of the disease as well3. …

Assessing Premature Arthritis In Sedc Mutant Mice, Shaela Avery, Dr. Robert Seegmiller

Journal of Undergraduate Research

A recently discovered collagen gene mutation, spondyloepiphiseal dysplasia congenita (sedc), is found on the Col2a1 gene in both mice and humans. The mouse mutation is molecularly similar to the human SEDC mutation, which causes premature osteoarthritis. Studies, such as this one, in mouse models provide a greater understanding of this recently discovered mutation and help in finding ways to prevent osteoarthritis in humans.

Histological And Ultrastructural Evidence Of Osteoarthritis In Mice Carrying A Semi-Dominant Mutation Of Col2a1, Victoria Ryder, Dr. Robert Seegmiller

Journal of Undergraduate Research

Mice heterozygous for the semi-dominant mutation disproportionate micromelia (Dmm) express mild chondrodysplasia by three weeks postnatally. This phenotype is attributed to a deletion of three contiguous nucleotides within the Col2A1 gene on mouse chromosome 15. The phenotype of Dmm/+ mice resembles that of human Stickler syndrome, which can be caused by mutations in the human COL2A1 gene.

Construction Of A Col11a1 Transgene And The Study Of The Col11a1 Mutation In Mice, Dana L. Murphy, Dr. Laura C. Bridgewater

Journal of Undergraduate Research

Collagen fibrils play an important role in proper skeletal development. Defective collagen can cause human skeletal disorders such as osteoarthritis that affects an estimated 20.7 million Americans. A particular mouse line, housed here at BYU, contains a mutation in the Col11a1 gene. This mutation results in defective type XI collagen, which is an important component of articular cartilage, and eventually leads to osteoarthritis (1).

Destabilization Of The Medial Meniscus: A Non-Genetic Approach To Inducing Osteoarthritis In Mice, Christopher Stockdale, Joshua Lloyd, Dr. Robert E. Seegiller

Journal of Undergraduate Research

Osteoarthritis (OA) is a common disease that causes discomfort and pain due to the degradation of the articular cartilage found on the surface of bones within the body’s joints. A properly functioning joint has a strong network of articular cartilage that can handle the constant strain caused by the use and movement of the joints. Individuals who suffer with OA have a compromised cartilage network that can result in softening of the cartilage, rough joint surfaces, fissures in the cartilage, and eventually direct bone on bone contact within the joint.

The Cerebral Cortex As An Effect Site For Anesthetic Induced Unconsciousness, Ryan Martin, David Busath

Journal of Undergraduate Research

General anesthetics are widely used today in medicine. Their molecular mechanisms however, still remain a mystery. For centuries, general anesthetics were thought to be “drugs without receptors” because of the lack of knowledge about their mechanism of action (Hemmings, et al., 2005). While some advances have been made by Neuroscientists and Biologists there is still a lot that is not known about general anesthetics. The exact location of general anesthetic action is thought to be complex, but two particular locations have been suggested—the cerebral cortex and the midbrain. Detailed understanding of where general anesthetics act is important because it would …

Orofacial Neuropathic Pain Mouse Model Induced By Trigeminal Inflammatory Compression (Tic) Of The Infraorbital Nerve, Fei Ma, Liping Zhang, Danielle Lyons, Karin N. Westlund

Physiology Faculty Publications

BACKGROUND: Trigeminal neuropathic pain attacks can be excruciating for patients, even after being lightly touched. Although there are rodent trigeminal nerve research models to study orofacial pain, few models have been applied to studies in mice. A mouse trigeminal inflammatory compression (TIC) model is introduced here which successfully and reliably promotes vibrissal whisker pad hypersensitivity.

RESULTS: The chronic orofacial neuropathic pain model is induced after surgical placement of chromic gut suture in the infraorbital nerve fissure in the maxillary bone. Slight compression and chemical effects of the chromic gut suture on the portion of the infraorbital nerve contacted cause mild …

Characterization Of Secretory Sphingomyelinase Activity, Lipoprotein Sphingolipid Content And Ldl Aggregation In Ldlr-/- Mice Fed On A High-Fat Diet, Gergana M. Deevska, Manjula Sunkara, Andrew J. Morris, Mariana N. Nikolova‑Karakashian

Physiology Faculty Publications

The propensity of LDLs (low-density lipoproteins) for aggregation and/or oxidation has been linked to their sphingolipid content, specifically the levels of SM (sphingomyelin) and ceramide. To investigate this association in vivo, ldlr (LDL receptor)-null mice (ldlr-/-) were fed on a modified (atherogenic) diet containing saturated fats and cholesterol. The diet led to significantly elevated SM content in all serum lipoproteins. In contrast, ceramide increased only in the LDL particles. MS-based analyses of the lipid acyl chain composition revealed a marked elevation in C16:0 fatty acid in SM and ceramide, consistent with the prevalence of palmitic acid in the modified diet. …

Atovaquone Ameliorate Gastrointestinal Toxoplasmosis Complications In A Pregnancy Model, Helieh S. Oz, Thomas Tobin

Physiology Faculty Publications

Background: Toxoplasma is an important source of foodborne hospitalization with no safe and effective therapy against chronic or congenital Toxopalsmosis. Atovaquone is a drug of choice but not approved for use in congenital Toxoplasmosis. We hypothesized atovaquone to be safe and effective against feto-maternal Toxoplasmosis.

Material/Methods: Programmed pregnant mice were i.p. infected with 50–2400 Tachyzoites from Type II strain (clone PTG). Dams were treated daily with atovaquone or sham and monitored for pain, and complications.

Results: Dams developed pain related abdominal hypersensitivity (allodynia) to mechanical stimuli in a Tachyzoites dose dependent manner. Infected dams were anemic and exhibited ascities and …

Genomics Of Mature And Immature Olfactory Sensory Neurons, Melissa D. Nickell, Patrick Breheny, Arnold J. Stromberg, Timothy S. Mcclintock

Physiology Faculty Publications

The continuous replacement of neurons in the olfactory epithelium provides an advantageous model for investigating neuronal differentiation and maturation. By calculating the relative enrichment of every mRNA detected in samples of mature mouse olfactory sensory neurons (OSNs), immature OSNs, and the residual population of neighboring cell types, and then comparing these ratios against the known expression patterns of >300 genes, enrichment criteria that accurately predicted the OSN expression patterns of nearly all genes were determined. We identified 847 immature OSN-specific and 691 mature OSN-specific genes. The control of gene expression by chromatin modification and transcription factors, and neurite growth, protein …

Peripheral Nerve Injury Increases Glutamate-Evoked Calcium Mobilization In Adult Spinal Cord Neurons, Suzanne Doolen, Camille B. Blake, Bret N. Smith, Bradley K. Taylor

Physiology Faculty Publications

BACKGROUND: Central sensitization in the spinal cord requires glutamate receptor activation and intracellular Ca2+ mobilization. We used Fura-2 AM bulk loading of mouse slices together with wide-field Ca2+ imaging to measure glutamate-evoked increases in extracellular Ca2+ to test the hypotheses that: 1. Exogenous application of glutamate causes Ca2+ mobilization in a preponderance of dorsal horn neurons within spinal cord slices taken from adult mice; 2. Glutamate-evoked Ca2+ mobilization is associated with spontaneous and/or evoked action potentials; 3. Glutamate acts at glutamate receptor subtypes to evoked Ca2+ transients; and 4. The magnitude of glutamate-evoked Ca2+ responses increases in the setting of …

Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction In A Mouse Model That Exhibits Age-Dependent Progression Of Alzheimer's Disease-Related Pathology, Adam D. Bachstetter, Christopher M. Norris, Pradoldej Sompol, Donna M. Wilcock, Danielle Goulding, Janna H. Neltner, Daret St. Clair, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that …

Mice Deficient In Gem Gtpase Show Abnormal Glucose Homeostasis Due To Defects In Beta-Cell Calcium Handling, Jenny E. Gunton, Mary Sisavanh, Rebecca A. Stokes, Jon Satin, Leslie S. Satin, Min Zhang, Sue M. Liu, Weikang Cai, Kim Cheng, Gregory J. Cooney, D. Ross Laybutt, Trina So, Juan-Carlos Molero, Shane T. Grey, Douglas A. Andres, Michael S. Rolph, Charles R. Mackay

Physiology Faculty Publications

AIMS AND HYPOTHESIS: Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo.

METHODS: Gem-deficient mice were generated and their metabolic phenotype characterised by in …

High And Low Active Inbred Mice Do Not Show Differential Expression In Potential Candidate Genes Associated With Voluntary Physical Activity, Michelle J. Dawes, David P. Ferguson, Greeshma S. Prabhu, Dr.Timothy Lightfoot

International Journal of Exercise Science: Conference Proceedings

Physical inactivity is associated with increased cardiovascular disease, obesity, type II diabetes and some types of cancers. Studies have shown that genetics play a significant role in the regulation of voluntary physical activity. However, these studies involve ad libitum access to wheel running, which may cause confounded results due to a training effect, especially in inherently high active animals. This study investigated the levels of gene expression of four potential candidate genes that have been noted to be expressed differentially between high and low active animals: Myostatin (Mstn), Calsequestrin 1 (Casq1), Glucose Transporter member 4 ( …