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Rev-Erb Agonism Improves Liver Pathology In A Mouse Model Of Nash, Kristine Griffett, Gonzalo Bedia-Diaz, Bahaa Elgendy, Thomas P. Burris Jan 2020

Rev-Erb Agonism Improves Liver Pathology In A Mouse Model Of Nash, Kristine Griffett, Gonzalo Bedia-Diaz, Bahaa Elgendy, Thomas P. Burris

Open Access Publications

Non-alcoholic fatty liver disease (NAFLD) affects a significant number of people worldwide and currently there are no pharmacological treatments. NAFLD often presents with obesity, insulin resistance, and in some cases cardiovascular diseases. There is a clear need for treatment options to alleviate this disease since it often progresses to much more the much more severe non-alcoholic steatohepatitis (NASH). The REV-ERB nuclear receptor is a transcriptional repressor that regulates physiological processes involved in the development of NAFLD including lipogenesis and inflammation. We hypothesized that pharmacologically activating REV-ERB would suppress the progression of fatty liver in a mouse model of NASH. Using …

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Focused Ultrasound For Safe And Effective Release Of Brain Tumor Biomarkers Into The Peripheral Circulation, Lifei Zhu, Arash Nazeri, Christopher Pham Pacia, Yimei Yue, Hong Chen Jan 2020

Focused Ultrasound For Safe And Effective Release Of Brain Tumor Biomarkers Into The Peripheral Circulation, Lifei Zhu, Arash Nazeri, Christopher Pham Pacia, Yimei Yue, Hong Chen

Open Access Publications

The development of noninvasive approaches for brain tumor diagnosis and monitoring continues to be a major medical challenge. Although blood-based liquid biopsy has received considerable attention in various cancers, limited progress has been made for brain tumors, at least partly due to the hindrance of tumor biomarker release into the peripheral circulation by the blood-brain barrier. Focused ultrasound (FUS) combined with microbubbles induced BBB disruption has been established as a promising technique for noninvasive and localized brain drug delivery. Building on this established technique, we propose to develop FUS-enabled liquid biopsy technique (FUS-LBx) to enhance the release of brain tumor …

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Cd4 Inhibits Helper T Cell Activation At Lower Affinity Threshold For Full-Length T Cell Receptors Than Single Chain Signaling Constructs, Deborah K Johnson, Wyatt Magoffin, Sheldon J Myers, Jordan G Finnell, John C Hancock, Taylor S Orton, Stephen P Persaud, Kenneth A Christensen, K Scott Weber Jan 2020

Cd4 Inhibits Helper T Cell Activation At Lower Affinity Threshold For Full-Length T Cell Receptors Than Single Chain Signaling Constructs, Deborah K Johnson, Wyatt Magoffin, Sheldon J Myers, Jordan G Finnell, John C Hancock, Taylor S Orton, Stephen P Persaud, Kenneth A Christensen, K Scott Weber

Open Access Publications

CD4

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Remember That Party Last Night? Examining The Effects Of Binge-Like Alcohol On Memory, Anna Thomas Jan 2020

Remember That Party Last Night? Examining The Effects Of Binge-Like Alcohol On Memory, Anna Thomas

Undergraduate Honors Thesis Collection

Alcohol is a widely available drug that is often abused. Studies have shown alcohol-induced memory loss in humans and animals; however, the large amount of alcohol often necessary to observe such loss and use of involuntary drinking paradigms in animals makes translation difficult. The current study was designed to look at voluntary binge-like drinking behavior and memory in rodents. We anticipated decreases in working memory function following consumption of binge-like alcohol in mice and expected a greater deficit in mice experiencing acute withdrawal during the memory task. The present study explored drinking behaviors in adult C57BL/6J mice (18 male, 18 …

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Rage Signaling As A Pharmacological Target In Amyotrophic Lateral Sclerosis, Liping Liu Jan 2020

Rage Signaling As A Pharmacological Target In Amyotrophic Lateral Sclerosis, Liping Liu

MUSC Theses and Dissertations

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of both upper and lower motor neurons. Astrocytes are key for maintaining central nervous system homeostasis and are important determinants of motor neuron fate in ALS. Accordingly, IPSC-derived astrocytes from ALS patients or astrocytes from diverse ALS mouse models, including mice overexpressing the ALS-linked mutant hSOD1G93A, induce motor neuron death in co-culture. Previously our lab reported that motor neurons isolated from receptor for advanced glycation end products (RAGE) knockout mice are resistant to the ALS-astrocyte derived neurotoxicity. Therefore, our working hypothesis states that inhibition of RAGE signaling can suppress astrocyte-mediated …

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Establishing A Myocardial Ischemia-Reperfusion Injury Model In Mice And Rats Using Left Anterior Descending Artery Ligation And Isolated Heart Experiments, Alexander Papa Jan 2020

Establishing A Myocardial Ischemia-Reperfusion Injury Model In Mice And Rats Using Left Anterior Descending Artery Ligation And Isolated Heart Experiments, Alexander Papa

PCOM Biomedical Studies Student Scholarship

Myocardial infarction (MI) is a leading cause of death globally, with over 730,000 cases each year in the United States alone. Factors involved in the prognosis of an MI include identification of the artery occluded, the time to reperfusion, the size of the infarct, and the degree of cardiomyocyte death. Thus, the treatment of MI typically involves targeting one or more of these factors. Timely opening of an occluded artery to reperfuse the ischemic tissue remains the mainstay treatment through either thrombolytic therapy, arterial stenting, or percutaneous coronary intervention. However, reperfusion itself may cause further damage through the generation of …

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Targeting Transcription Factors Xbp-1 And Fli-1 As Novel Translational Strategies To Control Graft-Versus-Host Disease, Steven Douglas Schutt Jan 2020

Targeting Transcription Factors Xbp-1 And Fli-1 As Novel Translational Strategies To Control Graft-Versus-Host Disease, Steven Douglas Schutt

MUSC Theses and Dissertations

Hematopoietic stem-cell transplantation (HCT) is a curative procedure for hematological malignancies, but chronic graft-versus-host disease (GVHD) remains a major complication after allogeneic HCT. Because donor B cells are essential for chronic GVHD (cGVHD) development and B cells are sensitive to endoplasmic reticulum stress, we hypothesized that the IRE-1α/XBP-1 pathway is required for B-cell activation and function in cGVHD. Here, we used mice deficient of XBP-1 specifically in B cells, and recipients transplanted with grafts containing XBP-1–deficient B cells displayed reduced cGVHD compared with controls that was associated with reduced B-cell activation and production of alloreactive antibodies. Prophylactic administration of B-I09 …

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Altered Circadian Rhythm And Neuroinflammation In Models Of Als: A Role For Nr1d1 And Fabp7, Kelby Killoy Jan 2020

Altered Circadian Rhythm And Neuroinflammation In Models Of Als: A Role For Nr1d1 And Fabp7, Kelby Killoy

MUSC Theses and Dissertations

Most physiological processes in mammals are subjected to daily oscillations governed by a circadian system. Circadian rhythm orchestrates metabolic pathways in a time-dependent manner and loss of circadian timekeeping has been associated with cellular and system-wide alterations in metabolism, redox homeostasis, and inflammation. Nuclear Receptor subfamily 1 group D member 1 (NR1D1) is a transcription factor that participates in the molecular clock that encodes circadian rhythms and links metabolism and inflammation to circadian cycles. Fatty acid binding protein 7 (FABP7), an NR1D1 target, is a regulator of lipid metabolism, energy homeostasis, and inflammation. FABP7 can regulate fatty acid uptake, transport, …

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Extracellular Mitochondria Released From Traumatized Brains Induced Platelet Procoagulant Activity, Zilong Zhao, Yuan Zhou, Tristan Hilton, Fanjian Li, Cha Han, Li Liu, Hengjie Yuan, Ying Li, Xin Xu, Xiaoping Wu, Fangyi Zhang, Perumal Thiagarajan, Andrew Cap, Fu-Dong Shi, Jianning Zhang, Jing-Fei Dong Jan 2020

Extracellular Mitochondria Released From Traumatized Brains Induced Platelet Procoagulant Activity, Zilong Zhao, Yuan Zhou, Tristan Hilton, Fanjian Li, Cha Han, Li Liu, Hengjie Yuan, Ying Li, Xin Xu, Xiaoping Wu, Fangyi Zhang, Perumal Thiagarajan, Andrew Cap, Fu-Dong Shi, Jianning Zhang, Jing-Fei Dong

Faculty, Staff and Students Publications

Coagulopathy often develops soon after acute traumatic brain injury and its cause remains poorly understood. We have shown that injured brains release cellular microvesicles that disrupt the endothelial barrier and induce consumptive coagulopathy. Morphologically intact extracellular mitochondria accounted for 55.2% of these microvesicles, leading to the hypothesis that these extracellular mitochondria are metabolically active and serve as a source of oxidative stress that activates platelets and renders them procoagulant. In testing this hypothesis experimentally, we found that the extracellular mitochondria purified from brain trauma mice and those released from brains subjected to freeze-thaw injury remained metabolically active and produced reactive …

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Sirt3 Promotes Lipophagy And Chaperon-Mediated Autophagy To Protect Hepatocytes Against Lipotoxicity, Tian Zhang, Jingxin Liu, Shengnan Shen, Qiang Tong, Xiaojun Ma, Ligen Lin Jan 2020

Sirt3 Promotes Lipophagy And Chaperon-Mediated Autophagy To Protect Hepatocytes Against Lipotoxicity, Tian Zhang, Jingxin Liu, Shengnan Shen, Qiang Tong, Xiaojun Ma, Ligen Lin

Faculty, Staff and Students Publications

Lipophagy is a lysosomal lipolytic pathway that complements the actions of cytosolic neutral lipases. Chaperon-mediated autophagy (CMA) triggers lipid droplets (LDs) breakdown, to initiate lipolysis via either cytosolic lipases or macroautophagy. SIRT3, a mitochondrial NAD+-dependent deacetylase, regulates the acetylation status and activity of many substrates involving in energy metabolism. However, the role of SIRT3 in regulating lipophagy is controversial. The current study showed that SIRT3 expression was decreased and the macroautophagy flux was blocked in the primary hepatocytes from high-fat diet fed mice and P/O (palmitic acid and oleic acid mixture) treated AML12 mouse hepatocytes, compared with the corresponding controls. …

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Targeting The Tumor Core: Hypoxia-Responsive Nanoparticles For The Delivery Of Chemotherapy To Pancreatic Tumors, Matthew I. Confeld, Babak Mamnoon, Li Feng, Heather Jensen Smith, Priyanka Ray, James Froberg, Jiha Kim, Michael A. Hollingsworth, Mohiuddin Quadir, Yongki Choi, Sanku Mallik Jan 2020

Targeting The Tumor Core: Hypoxia-Responsive Nanoparticles For The Delivery Of Chemotherapy To Pancreatic Tumors, Matthew I. Confeld, Babak Mamnoon, Li Feng, Heather Jensen Smith, Priyanka Ray, James Froberg, Jiha Kim, Michael A. Hollingsworth, Mohiuddin Quadir, Yongki Choi, Sanku Mallik

Journal Articles: Eppley Institute

In pancreatic ductal adenocarcinoma (PDAC), early onset of hypoxia triggers remodeling of the extracellular matrix, epithelial-to-mesenchymal transition, increased cell survival, the formation of cancer stem cells, and drug resistance. Hypoxia in PDAC is also associated with the development of collagen-rich, fibrous extracellular stroma (desmoplasia), resulting in severely impaired drug penetration. To overcome these daunting challenges, we created polymer nanoparticles (polymersomes) that target and penetrate pancreatic tumors, reach the hypoxic niches, undergo rapid structural destabilization, and release the encapsulated drugs. In vitro studies indicated a high cellular uptake of the polymersomes and increased cytotoxicity of the drugs under hypoxia compared to …

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Assessment Of In Vivo Muscle Force In The R6/2 Mouse Model Of Huntington's Disease Using Newly Designed Force Rig, Steven Russell Alan Burke Jan 2020

Assessment Of In Vivo Muscle Force In The R6/2 Mouse Model Of Huntington's Disease Using Newly Designed Force Rig, Steven Russell Alan Burke

Browse all Theses and Dissertations

In this thesis, we develop a system to study in vivo muscle function in a mouse model of Huntington’s disease that allows for the recording of muscle force by stimulating the motor nerves or the muscles directly after a nerve block. This allows us to distinguish between defects in the nerve, such as problems with vesicle release, and primary muscle defects, such as altered intracellular calcium homeostasis. We hypothesize that there are primary defects in R6/2 skeletal muscle that are separate from neurodegeneration or defects in the CNS. In this case, we should see defects in muscle force generation during …

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Validation Of Ninein As An Ethanol-Related Quantitative Trait Gene: Reassessment, Design, And Functional Validation Of Reference Genes For Qpcr Analysis Of Brain Tissue In Mice, Jessica L. Jurmain Jan 2020

Validation Of Ninein As An Ethanol-Related Quantitative Trait Gene: Reassessment, Design, And Functional Validation Of Reference Genes For Qpcr Analysis Of Brain Tissue In Mice, Jessica L. Jurmain

Theses and Dissertations

The increasing use of quantitative real-time polymerase chain reaction (qPCR) as a method for quantifying gene expression has led to an increased demand for standardization of data analysis methods to ensure accurate reporting and robust, reproducible results. The exponential nature of qPCR amplification results in the potential magnification of what are usually very small sources of error. Relative gene expression calculations circumvent this issue by normalizing target gene expression data to within-sample expression of a previously validated, stably expressed reference gene or genes. Multiple studies discussed herein have found that qPCR data are more reliable and reproducible when multiple reference …

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Novel Duel Mtor Inhibitors/Ampk Activators Improve Therapeutic Efficacy Of Doxorubicin And Ameliorate Its Associated Cardiotoxicity In Mice, Sahak Eric Hovsepian Jan 2020

Novel Duel Mtor Inhibitors/Ampk Activators Improve Therapeutic Efficacy Of Doxorubicin And Ameliorate Its Associated Cardiotoxicity In Mice, Sahak Eric Hovsepian

Theses and Dissertations

Triple-negative breast cancer (TNBC) is a particularly aggressive subset of breast cancer that has a molecular expression profile which lacks the estrogen receptor (ER), progesterone receptor (ER), and human epidermal growth factor receptor type 2 (HER2). No targeted treatment options currently exist for TNBC, unlike other types of breast cancer, and therefore survival rates are far lower for these patients. The current treatment for TNBC is systemic anthracycline chemotherapy, typically doxorubicin (DOX), which has great clinical efficacy in increasing survival. However, DOX induces a dose-dependent progressive cardiomyopathy, which can present years and up to decades after the last treatment. This …

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Granulosa Cell Proliferation Is Inhibited By Pge2 In The Primate Ovulatory Follicle, Patric S. Lundberg, Gil J. Moskowitz, Carmel Bellacose, Esra Demirel, Heidi A. Trau, Diane M. Duffy Jan 2020

Granulosa Cell Proliferation Is Inhibited By Pge2 In The Primate Ovulatory Follicle, Patric S. Lundberg, Gil J. Moskowitz, Carmel Bellacose, Esra Demirel, Heidi A. Trau, Diane M. Duffy

Computer Science Faculty Publications

Prostaglandin E2 (PGE2) is a key paracrine mediator of ovulation. Few specific PGE2-regulated gene products have been identified, so we hypothesized that PGE2 may regulate the expression and/or activity of a network of proteins to promote ovulation. To test this concept, Ingenuity Pathway Analysis (IPA) was used to predict PGE2-regulated functionalities in the primate ovulatory follicle. Cynomolgus macaques underwent ovarian stimulation. Follicular granulosa cells were obtained before (0 h) or 36 h after an ovulatory dose of human chorionic gonadotropin (hCG), with ovulation anticipated 37-40 h after hCG. Granulosa cells were obtained from additional monkeys 36 h after treatment with …

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Characterizing Humidity, Sex, And B-Cell Gene Regulation In Fungal Allergic Asthma, Emma Claire Kusick Jan 2020

Characterizing Humidity, Sex, And B-Cell Gene Regulation In Fungal Allergic Asthma, Emma Claire Kusick

Microbiological Sciences

Asthma is a debilitating lung disease that affects nearly 300 million people worldwide. Environments with high humidity and subsequent mold exposure often trigger allergic asthma. Sex differences have been reported in the incidence, prevalence, and severity of asthma. B-lymphocytes are recruited in high numbers to the allergic lung in response to the inhalation of Aspergillus fumigatus mold spores (conidia). In this work, we used a mouse model of allergic fungal asthma to assess environmental humidity, sex, and B-lymphocytes in an inhalational model of allergic fungal asthma. Our results showed that animals sensitized in low humidity conditions had no airway hyperresponsiveness …

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Client Processing Is Altered By Novel Myopathy-Causing Mutations In The Hsp40 J Domain, Melanie Y. Pullen, Conrad C. Weihl, Heather L. True Jan 2020

Client Processing Is Altered By Novel Myopathy-Causing Mutations In The Hsp40 J Domain, Melanie Y. Pullen, Conrad C. Weihl, Heather L. True

Open Access Publications

The misfolding and aggregation of proteins is often implicated in the development and progression of degenerative diseases. Heat shock proteins (HSPs), such as the ubiquitously expressed Type II Hsp40 molecular chaperone, DNAJB6, assist in protein folding and disaggregation. Historically, mutations within the DNAJB6 G/F domain have been associated with Limb-Girdle Muscular Dystrophy type 1D, now referred to as LGMDD1, a dominantly inherited degenerative disease. Recently, novel mutations within the J domain of DNAJB6 have been reported in patients with LGMDD1. Since novel myopathy-causing mutations in the Hsp40 J domain have yet to be characterized and both the function of DNAJB6 …

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Small Molecules That Inhibit Tnf Signalling By Stabilising An Asymmetric Form Of The Trimer, James O'Connell, John Porter, Boris Kroeplien, Tim Norman, Stephen Rapecki, Rachel E. Davis, David Mcmillan, Tracy Arakaki, Alex Burgin, David Fox Iii, Tom Ceska, Fabien Lecomte, Alison Maloney, Alex Vugler, Bruce Carrington, Benjamin P. Cossins, Tim Bourne, Alastair Lawson Dec 2019

Small Molecules That Inhibit Tnf Signalling By Stabilising An Asymmetric Form Of The Trimer, James O'Connell, John Porter, Boris Kroeplien, Tim Norman, Stephen Rapecki, Rachel E. Davis, David Mcmillan, Tracy Arakaki, Alex Burgin, David Fox Iii, Tom Ceska, Fabien Lecomte, Alison Maloney, Alex Vugler, Bruce Carrington, Benjamin P. Cossins, Tim Bourne, Alastair Lawson

Faculty Publications

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for …

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Regional Gene Repression By Dna Double-Strand Breaks In G1 Phase Cells, Caitlin E. Purman, Patrick L. Collins, Sofia I. Porter, Ankita Saini, Harshath Gupta, Barry P. Sleckman, Eugene M. Oltz Dec 2019

Regional Gene Repression By Dna Double-Strand Breaks In G1 Phase Cells, Caitlin E. Purman, Patrick L. Collins, Sofia I. Porter, Ankita Saini, Harshath Gupta, Barry P. Sleckman, Eugene M. Oltz

Open Access Publications

DNA damage responses (DDR) to double-strand breaks (DSBs) alter cellular transcription programs at the genome-wide level. Through processes that are less well understood, DSBs also alter transcriptional responses locally, which may be important for efficient DSB repair. Here, we developed an approach to elucidate the

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Clearance Of Chikungunya Virus Infection In Lymphoid Tissues Is Promoted By Treatment With An Agonistic Anti-Cd137 Antibody, Jun P Hong, Mary K Mccarthy, Bennett J Davenport, Thomas E Morrison, Michael S Diamond Dec 2019

Clearance Of Chikungunya Virus Infection In Lymphoid Tissues Is Promoted By Treatment With An Agonistic Anti-Cd137 Antibody, Jun P Hong, Mary K Mccarthy, Bennett J Davenport, Thomas E Morrison, Michael S Diamond

Open Access Publications

CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV …

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Distinct Roles Of Interferon Alpha And Beta In Controlling Chikungunya Virus Replication And Modulating Neutrophil-Mediated Inflammation, Lindsey E Cook, Marissa C Locke, Alissa R Young, Kristen Monte, Matthew L Hedberg, Raeann M Shimak, Kathleen C F Sheehan, Deborah J Veis, Michael S Diamond, Deborah J Lenschow Dec 2019

Distinct Roles Of Interferon Alpha And Beta In Controlling Chikungunya Virus Replication And Modulating Neutrophil-Mediated Inflammation, Lindsey E Cook, Marissa C Locke, Alissa R Young, Kristen Monte, Matthew L Hedberg, Raeann M Shimak, Kathleen C F Sheehan, Deborah J Veis, Michael S Diamond, Deborah J Lenschow

Open Access Publications

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice …

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Ultrafast Two-Photon Imaging Of A High-Gain Voltage Indicator In Awake Behaving Mice, Vincent Villette, Mariya Chavarha, Ivan K Dimov, Jonathan Bradley, Lagnajeet Pradhan, Benjamin Mathieu, Stephen W Evans, Simon Chamberland, Dongqing Shi, Renzhi Yang, Benjamin B Kim, Annick Ayon, Abdelali Jalil, François St-Pierre, Mark J Schnitzer, Guoqiang Bi, Katalin Toth, Jun Ding, Stéphane Dieudonné, Michael Z Lin Dec 2019

Ultrafast Two-Photon Imaging Of A High-Gain Voltage Indicator In Awake Behaving Mice, Vincent Villette, Mariya Chavarha, Ivan K Dimov, Jonathan Bradley, Lagnajeet Pradhan, Benjamin Mathieu, Stephen W Evans, Simon Chamberland, Dongqing Shi, Renzhi Yang, Benjamin B Kim, Annick Ayon, Abdelali Jalil, François St-Pierre, Mark J Schnitzer, Guoqiang Bi, Katalin Toth, Jun Ding, Stéphane Dieudonné, Michael Z Lin

Faculty, Staff and Students Publications

Optical interrogation of voltage in deep brain locations with cellular resolution would be immensely useful for understanding how neuronal circuits process information. Here, we report ASAP3, a genetically encoded voltage indicator with 51% fluorescence modulation by physiological voltages, submillisecond activation kinetics, and full responsivity under two-photon excitation. We also introduce an ultrafast local volume excitation (ULoVE) method for kilohertz-rate two-photon sampling in vivo with increased stability and sensitivity. Combining a soma-targeted ASAP3 variant and ULoVE, we show single-trial tracking of spikes and subthreshold events for minutes in deep locations, with subcellular resolution and with repeated sampling over days. In the …

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Chronic Muscle Weakness And Mitochondrial Dysfunction In The Absence Of Sustained Atrophy In A Preclinical Sepsis Model, Allison M. Owen, Samir P. Patel, Jeffrey D. Smith, Beverly K. Balasuriya, Stephanie F. Mori, Gregory S. Hawk, Arnold J. Stromberg, Naohide Kuriyama, Masao Kaneki, Alexander G. Rabchevsky, Timothy A. Butterfield, Karyn A. Esser, Charlotte A. Peterson, Marlene E. Starr, Hiroshi Saito Dec 2019

Chronic Muscle Weakness And Mitochondrial Dysfunction In The Absence Of Sustained Atrophy In A Preclinical Sepsis Model, Allison M. Owen, Samir P. Patel, Jeffrey D. Smith, Beverly K. Balasuriya, Stephanie F. Mori, Gregory S. Hawk, Arnold J. Stromberg, Naohide Kuriyama, Masao Kaneki, Alexander G. Rabchevsky, Timothy A. Butterfield, Karyn A. Esser, Charlotte A. Peterson, Marlene E. Starr, Hiroshi Saito

Physiology Faculty Publications

Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of …

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Defining The Layers Of A Sensory Cilium With Storm And Cryoelectron Nanoscopy, Michael A Robichaux, Valencia L Potter, Zhixian Zhang, Feng He, Jun Liu, Michael F Schmid, Theodore G Wensel Nov 2019

Defining The Layers Of A Sensory Cilium With Storm And Cryoelectron Nanoscopy, Michael A Robichaux, Valencia L Potter, Zhixian Zhang, Feng He, Jun Liu, Michael F Schmid, Theodore G Wensel

Faculty, Staff and Students Publications

Primary cilia carry out numerous signaling and sensory functions, and defects in them, "ciliopathies," cause a range of symptoms, including blindness. Understanding of their nanometer-scale ciliary substructures and their disruptions in ciliopathies has been hindered by limitations of conventional microscopic techniques. We have combined cryoelectron tomography, enhanced by subtomogram averaging, with superresolution stochastic optical reconstruction microscopy (STORM) to define subdomains within the light-sensing rod sensory cilium of mouse retinas and reveal previously unknown substructures formed by resident proteins. Domains are demarcated by structural features such as the axoneme and its connections to the ciliary membrane, and are correlated with molecular …

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Gut Microbiota: From The Forgotten Organ To A Potential Key Player In The Pathology Of Alzheimer's Disease, Dong-Oh Seo, David M Holtzman Nov 2019

Gut Microbiota: From The Forgotten Organ To A Potential Key Player In The Pathology Of Alzheimer's Disease, Dong-Oh Seo, David M Holtzman

Open Access Publications

More than 300 years ago, Antony van Leewenhoeck first described observing single-celled microorganisms, which he termed "animalcules," examining his saliva under a microscope. Although the idea of the coexistence of microorganisms in our body is not new, we have only recently been able to investigate their ecological relationship to our body, with the development of high-throughput molecular techniques. The diverse microorganism communities residing in our guts are established and maintained by complex interactions among microorganisms and their host. Notably, their alteration has been implicated in influencing various diseases including neurological diseases. Alzheimer's disease (AD) is the most common cause of …

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Interleukin 1 Alpha Administration Is Neuroprotective And Neuro-Restorative Following Experimental Ischemic Stroke, Kathleen E. Salmeron, Michael E. Maniskas, Danielle N. Edwards, Raymond Wong, Ivana Rajkovic, Amanda L. Trout, Abir A. Rahman, Samantha Hamilton, Justin F. Fraser, Emmanuel Pinteaux, Gregory J. Bix Nov 2019

Interleukin 1 Alpha Administration Is Neuroprotective And Neuro-Restorative Following Experimental Ischemic Stroke, Kathleen E. Salmeron, Michael E. Maniskas, Danielle N. Edwards, Raymond Wong, Ivana Rajkovic, Amanda L. Trout, Abir A. Rahman, Samantha Hamilton, Justin F. Fraser, Emmanuel Pinteaux, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et …

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Microarray Embedding/Sectioning For Parallel Analysis Of 3d Cell Spheroids., Jonathan Gabriel, David Brennan, Jennifer H Elisseeff, Vincent Beachley Nov 2019

Microarray Embedding/Sectioning For Parallel Analysis Of 3d Cell Spheroids., Jonathan Gabriel, David Brennan, Jennifer H Elisseeff, Vincent Beachley

Henry M. Rowan College of Engineering Departmental Research

Three-dimensional cell spheroid models can be used to predict the effect of drugs and therapeutics and to model tissue development and regeneration. The utility of these models is enhanced by high throughput 3D spheroid culture technologies allowing researchers to efficiently culture numerous spheroids under varied experimental conditions. Detailed analysis of high throughput spheroid culture is much less efficient and generally limited to narrow outputs, such as metabolic viability. We describe a microarray approach that makes traditional histological embedding/sectioning/staining feasible for large 3D cell spheroid sample sets. Detailed methodology to apply this technology is provided. Analysis of the technique validates the …

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Tfeb Activation In Macrophages Attenuates Postmyocardial Infarction Ventricular Dysfunction Independently Of Atg5-Mediated Autophagy, Ali Javaheri, Geetika Bajpai, Antonino Picataggi, Smrithi Mani, Layla Foroughi, Hosannah Evie, Attila Kovacs, Carla J Weinheimer, Krzystztof Hyrc, Qingli Xiao, Andrea Ballabio, Jin-Moo Lee, Scot J Matkovich, Babak Razani, Joel D Schilling, Kory J Lavine, Abhinav Diwan Nov 2019

Tfeb Activation In Macrophages Attenuates Postmyocardial Infarction Ventricular Dysfunction Independently Of Atg5-Mediated Autophagy, Ali Javaheri, Geetika Bajpai, Antonino Picataggi, Smrithi Mani, Layla Foroughi, Hosannah Evie, Attila Kovacs, Carla J Weinheimer, Krzystztof Hyrc, Qingli Xiao, Andrea Ballabio, Jin-Moo Lee, Scot J Matkovich, Babak Razani, Joel D Schilling, Kory J Lavine, Abhinav Diwan

Open Access Publications

Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome activation and IL-1β secretion are implicated in myocardial infarction (MI) and resultant heart failure; however, little is known about how macrophage lysosomes regulate these processes. In mice subjected to cardiac ischemia/reperfusion (IR) injury and humans with ischemic cardiomyopathy, we observed evidence of lysosomal impairment in macrophages. Inducible macrophage-specific overexpression of transcription factor EB (TFEB), a master regulator of lysosome biogenesis (Mϕ-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1β compared with controls. Surprisingly, neither inflammasome suppression nor Mϕ-TFEB-mediated attenuation …

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Vav1 Inhibits Rankl-Induced Osteoclast Differentiation And Bone Resorption., Jin Sun Jang, In Soon Kang, Young-Nam Cha, Zang Hee Lee, Mary C Dinauer, Young-June Kim, Chaekyun Kim Nov 2019

Vav1 Inhibits Rankl-Induced Osteoclast Differentiation And Bone Resorption., Jin Sun Jang, In Soon Kang, Young-Nam Cha, Zang Hee Lee, Mary C Dinauer, Young-June Kim, Chaekyun Kim

Open Access Publications

Vav1 is a Rho/Rac guanine nucleotide exchange factor primarily expressed in hematopoietic cells. In this study, we investigated the potential role of Vav1 in osteoclast (OC) differentiation by comparing the ability of bone marrow mononuclear cells (BMMCs) obtained from Vav1-deficient (Vav1-/-) and wild-type (WT) mice to differentiate into mature OCs upon stimulation with macrophage colony stimulating factor and receptor activator of nuclear kappa B ligand in vitro. Our results suggested that Vav1 deficiency promoted the differentiation of BMMCs into OCs, as indicated by the increased expression of tartrate-resistant acid phosphatase, cathepsin K, and calcitonin receptor. Therefore, Vav1 may play a …

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Sirna Targeting And Treatment Of Gastrointestinal Diseases., Rachel Chevalier Nov 2019

Sirna Targeting And Treatment Of Gastrointestinal Diseases., Rachel Chevalier

Manuscripts, Articles, Book Chapters and Other Papers

RNA interference via small interfering RNA (siRNA) offers opportunities to precisely target genes that contribute to gastrointestinal (GI) pathologies, such as inflammatory bowel disease, celiac, and esophageal scarring. Delivering the siRNA to the GI tract proves challenging as the harsh environment of the intestines degrades the siRNA before it can reach its target or blocks its entry into its site of action in the cytoplasm. Additionally, the GI tract is large and disease is often localized to a specific site. This review discusses polymer and lipid-based delivery systems for protection and targeting of siRNA therapies to the GI tract to …

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