Medical Sciences Commons^™

Editorial: The Metabolism Of The Neuron-Glia Unit, Yannick Poitelon, Lance A. Johnson, Marie-Ève Tremblay

Physiology Faculty Publications

No abstract provided.

Ethanol And Opioids Do Not Act Synergistically To Depress Excitation In Carotid Body Type I Cells, Ryan J. Rakoczy, Kajal Kamra, Yoon-Jae Yi, Christopher N. Wyatt

Neuroscience, Cell Biology & Physiology Faculty Publications

The combination of opioids and ethanol can synergistically depress breathing and the acute ventilatory response to hypoxia. Multiple studies have shown that the underlying mechanisms for this may involve calcium channel inhibition in central neurons. But we have previously identified opioid receptors in the carotid bodies and shown that their activation inhibits calcium influx into the chemosensitive cells. Given that the carotid bodies contribute to the drive to breathe and underpin the acute hypoxic ventilatory response, we hypothesized that ethanol and opioids may act synergistically in these peripheral sensory organs to further inhibit calcium influx and therefore inhibit ventilation.

Methods …

Apoε4 Lowers Energy Expenditure In Females And Impairs Glucose Oxidation By Increasing Flux Through Aerobic Glycolysis, Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson

Physiology Faculty Publications

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.

METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.

RESULTS: Single-cell …

A Cancer Ubiquitome Landscape Identifies Metabolic Reprogramming As Target Of Parkin Tumor Suppression, Ekta Agarwal, Aaron R Goldman, Hsin-Yao Tang, Andrew V Kossenkov, Jagadish C Ghosh, Lucia Languino, Valentina Vaira, David W Speicher, Dario C Altieri

Department of Cancer Biology Faculty Papers

Changes in metabolism that affect mitochondrial and glycolytic networks are hallmarks of cancer, but their impact in disease is still elusive. Using global proteomics and ubiquitome screens, we now show that Parkin, an E3 ubiquitin ligase and key effector of mitophagy altered in Parkinson's disease, shuts off mitochondrial dynamics and inhibits the non-oxidative phase of the pentose phosphate pathway. This blocks tumor cell movements, creates metabolic and oxidative stress, and inhibits primary and metastatic tumor growth. Uniformly down-regulated in cancer patients, Parkin tumor suppression requires its E3 ligase function, is reversed by antioxidants, and is independent of mitophagy. These data …

The Effects Of Estrogen In The Glucoregulatory Response To Exercise In Type 1 Diabetes, Mitchell James Sammut

Undergraduate Student Research Internships Conference

Regular exercise has shown to benefit the health of individuals with type 1 diabetes mellitus (T1DM). However, a barrier to regular exercise for this population is the fear of low blood glucose (BG) levels, also known as hypoglycemia. Hypoglycemia can result in short and long-term side-effects, such as recurring loss of consciousness or in severe cases death.

In non-diabetics, sex-related differences in fuel selection during exercise are well established. Women shift towards using fats as fuel whereas men rely mostly on sugars (i.e., carbohydrates) for energy production. Exercise during the luteal phase of the female menstrual cycle, where estrogen levels …

Metabolic-Epigenetic Regulation Of Macrophage Polarization., Jordan T. Noe

Electronic Theses and Dissertations

Tumor-associated macrophages polarized to an M2 phenotype (M2-TAMs) promote neo-angiogenesis, tumor-stromal matrix remodeling, and immuno-evasion, which, collectively, contribute to immunotherapeutic resistance and reduced cancer patient survival. Highly glycolytic “Warburg” cancer cells produce lactate that independently drives naïve M0→immunosuppressive M2 (M0→M2) macrophage polarization, but the mechanisms have not been fully elucidated. The atypical cytokine macrophage migration inhibitory factor (MIF) is a fundamental underlying requirement for immunosuppressive M2 macrophage polarization. Still, it is unknown whether a molecular link exists between lactate-supported and MIF-dependent M2 macrophage polarization. Using a combination of gene expression assays, chromatin immunoprecipitation, and metabolomic analyses, we identified that M2 …

Mri Of Structural & Functional Changes Associated With Western Diet Consumption, Lauren M. Smith

Electronic Thesis and Dissertation Repository

The Western diet (WD) is a high-fat, high-sugar diet increasingly common in the Western world and is associated with adverse effects in many organs, though the mechanisms behind these changes are unclear. Magnetic resonance imaging (MRI) techniques that provide structural and functional information non-invasively were used to investigate the effect of the WD on the liver and placenta in a guinea pig model.

The WD leads to a manifestation of the metabolic syndrome in the liver known as non-alcoholic fatty liver disease (NAFLD). Fat-fraction MRI was used to confirm the onset of NAFLD in a guinea pig model fed a …

Aberrant Azin2 And Polyamine Metabolism Precipitates Tau Neuropathology, Leslie A. Sandusky-Beltran, Andrii Kovalenko, Devon S. Placides, Kevin Ratnasamy, Chao Ma, Jerry B. Hunt, Huimin Liang, John Ivan T. Calahatian, Camilla Michalski, Margaret Fahnestock, Laura J. Blair, April L. Darling, Jeremy D. Baker, Sarah N. Fontaine, Chad A. Dickey, Joshua J. Gamsby, Kevin R. Nash, Erin L. Abner, Maj-Linda B. Selenica, Daniel C. Lee

Sanders-Brown Center on Aging Faculty Publications

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell’s response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer’s disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to …

Homeostatic T Cell Receptor Interactions With Self-Peptide Tune Cd4+ T Cell Function, Juliet Marie Bartleson

Arts & Sciences Electronic Theses and Dissertations

Homeostatic T Cell Receptor Interactions with Self-Peptide Tune CD4+ T Cell Function

by

Juliet Marie Bartleson

Doctor of Philosophy in Biology and Biomedical Sciences

Immunology

Washington University in St. Louis, 2021

Professor Paul M. Allen, Chair

Mature CD4+ T cells circulate throughout peripheral secondary lymphoid organs using their T cell receptor (TCR) to surveil peptide presented on major histocompatibility complex class II molecules (pMHC) in search of cognate, antigenic peptide. In the absence of an immune challenge, however, the TCR is continuously interacting with self-pMHC, which induces a relatively weak TCR signal known as tonic signaling. These homeostatic TCR:self-pMHC interactions …

Mitochondria Exert Age-Divergent Effects On Recovery From Spinal Cord Injury, Andrew N. Stewart, Katelyn E. Mcfarlane, Hemendra J. Vekaria, William M. Bailey, Stacey A. Slone, Lauren A. Tranthem, Bei Zhang, Samir P. Patel, Patrick G. Sullivan, John C. Gensel

Physiology Faculty Publications

The extent that age-dependent mitochondrial dysfunction drives neurodegeneration is not well understood. This study tested the hypothesis that mitochondria contribute to spinal cord injury (SCI)-induced neurodegeneration in an age-dependent manner by using 2,4-dinitrophenol (DNP) to uncouple electron transport, thereby increasing cellular respiration and reducing reactive oxygen species (ROS) production. We directly compared the effects of graded DNP doses in 4- and 14-month-old (MO) SCI-mice and found DNP to have increased efficacy in mitochondria isolated from 14-MO animals. In vivo, all DNP doses significantly exacerbated 4-MO SCI neurodegeneration coincident with worsened recovery. In contrast, low DNP doses (1.0-mg/kg/day) improved tissue …

Radiation Induces Metabolic Dysregulation In Pulmonary Fibroblasts, Josly Pierre-Louis, Margaret A. T. Freeberg, Jane K. Rebman, Thomas H. Thatcher, Patricia J. Sime

Graduate Research Posters

Rationale: Exposure of the lung to ionizing radiation, such as during radiotherapy, can result in pulmonary fibrosis (PF), which has few treatment options. PF is characterized by an accumulation of extracellular matrix proteins that form scar tissue, resulting in dyspnea, disruption of gas exchange, and even death. We and others have shown that metabolic reprogramming is a hallmark of idiopathic pulmonary fibrosis (IPF). IPF lung tissue, and lung fibroblasts treated with TGF-β, exhibit increased aerobic glycolysis with increased expression of lactate dehydrogenase A (LDHA) and excess production of lactate, leading to reduced extracellular pH that activates latent TGF-β. Here, we …

Mechanisms And Therapeutic Interventions For Breast Cancer-Induced Fatigue And Mitochondrial Dysfunction, David Andrew Stanton

Graduate Theses, Dissertations, and Problem Reports

According to the latest statistics from the National Cancer Institute (NCI), about 1 in 8 U.S. women (~13%) will develop invasive breast cancer over the course of their lifetime. This translates to an estimated 268,600 new cases of breast cancer for the year 2019, and these diagnoses will collectively make up 15% of all new cancer cases across all cancer types. The majority of these women will experience the often-debilitating symptom of breast cancer-induced fatigue. these patients often have difficulty performing normal activities of daily living, have decreased tolerance to traditional tumor-directed therapies, and have higher rates of cancer recurrence. …

Transcriptional Regulation And Islet Transplantation Advantages Of Brown Adipose Tissue, Jessica D. Kepple

All ETDs from UAB

Metabolic disease encompasses various disorders, including obesity and diabetes, that negatively impact glucose and lipid homeostasis and increase the risk of co-morbidities. Adipose tissue, which regulates whole-body energy balance and acts as a specialized endocrine tissue, is negatively affected by obesity and diabetes. Brown adipose tissue (BAT) functions to dissipate excess energy as heat and therefore is an attractive target against metabolic disease. To develop more effective therapeutic strategies, BAT physiology and genetic regulatory mechanisms need to be better understood. This dissertation highlights studies seeking to illuminate novel transcriptional regulation and islet transplantation applications of BAT. We investigated the requirement …