Open Access. Powered by Scholars. Published by Universities.®

Biochemistry, Biophysics, and Structural Biology Commons

Open Access. Powered by Scholars. Published by Universities.®

Physiology

2016

Institution
Keyword
Publication
Publication Type
File Type

Articles 1 - 30 of 67

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Phosphorylation Of The Mdm2 Oncoprotein By The C-Abl Tyrosine Kinase Regulates P53 Tumor Suppression And The Radiosensitivity Of Mice, Michael I. Carr, Justine E. Roderick, Hong Zhang, Bruce A. Woda, Michelle A. Kelliher, Stephen N. Jones Dec 2016

Phosphorylation Of The Mdm2 Oncoprotein By The C-Abl Tyrosine Kinase Regulates P53 Tumor Suppression And The Radiosensitivity Of Mice, Michael I. Carr, Justine E. Roderick, Hong Zhang, Bruce A. Woda, Michelle A. Kelliher, Stephen N. Jones

UMass Metabolic Network Publications

The p53 tumor suppressor acts as a guardian of the genome by preventing the propagation of DNA damage-induced breaks and mutations to subsequent generations of cells. We have previously shown that phosphorylation of the Mdm2 oncoprotein at Ser394 by the ATM kinase is required for robust p53 stabilization and activation in cells treated with ionizing radiation, and that loss of Mdm2 Ser394 phosphorylation leads to spontaneous tumorigenesis and radioresistance in Mdm2S394A mice. Previous in vitro data indicate that the c-Abl kinase phosphorylates Mdm2 at the neighboring residue (Tyr393) in response to DNA damage to regulate p53-dependent apoptosis. In this present ...


Wzb117 (2-Fluoro-6-(M-Hydroxybenzoyloxy) Phenyl M-Hydroxybenzoate) Inhibits Glut1-Mediated Sugar Transport By Binding Reversibly At The Exofacial Sugar Binding Site, Ogooluwa A. Ojelabi, Kenneth P. Lloyd, Andrew Simon, Julie K. De Zutter, Anthony Carruthers Dec 2016

Wzb117 (2-Fluoro-6-(M-Hydroxybenzoyloxy) Phenyl M-Hydroxybenzoate) Inhibits Glut1-Mediated Sugar Transport By Binding Reversibly At The Exofacial Sugar Binding Site, Ogooluwa A. Ojelabi, Kenneth P. Lloyd, Andrew Simon, Julie K. De Zutter, Anthony Carruthers

UMass Metabolic Network Publications

WZB117 (2-fluoro-6-(m-hydroxybenzoyloxy) phenyl m-hydroxybenzoate) inhibits passive sugar transport in human erythrocytes and cancer cell lines and, by limiting glycolysis, inhibits tumor growth in mice. This study explores how WZB117 inhibits the erythrocyte sugar transporter glucose transport protein 1 (GLUT1) and examines the transporter isoform specificity of inhibition. WZB117 reversibly and competitively inhibits erythrocyte 3-O-methylglucose (3MG) uptake with Ki(app) = 6 mum but is a noncompetitive inhibitor of sugar exit. Cytochalasin B (CB) is a reversible, noncompetitive inhibitor of 3MG uptake with Ki(app) = 0.3 mum but is a competitive inhibitor of sugar exit indicating that WZB117 and CB ...


Inflammatory Gene Expression In Women Diagnosed With Polycystic Ovarian Syndrome, Myles K. Taylor Dec 2016

Inflammatory Gene Expression In Women Diagnosed With Polycystic Ovarian Syndrome, Myles K. Taylor

Electronic Thesis Collection

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The pathophysiology of PCOS has conventionally thought to originate from androgen excess. However, recent evidence suggests that androgen excess is a downstream consequence to inflammatory dysregulation and subsequent metabolic abnormalities. Inflammatory mRNA gene expression of TNFa and IL-1ß in mononuclear cells isolated from women diagnosed with PCOS was explored using qPCR. Additionally, the correlations between body mass index (BMI) and fasting glucose on mRNA expression of TNFa and IL-1ß were explored. mRNA expression of both TNFa and IL-1ß were found to be significantly higher in PCOS ...


Pgc-1alpha Dictates Endothelial Function Through Regulation Of Enos Expression, Siobhan M. Craige, Swenja Kroller-Schon, Chunying Li, Shashi Kant, Shenghe Cai, Kai Chen, Mayur M. Contractor, Yongmei Pei, Eberhard Schulz, John F. Keaney Jr. Dec 2016

Pgc-1alpha Dictates Endothelial Function Through Regulation Of Enos Expression, Siobhan M. Craige, Swenja Kroller-Schon, Chunying Li, Shashi Kant, Shenghe Cai, Kai Chen, Mayur M. Contractor, Yongmei Pei, Eberhard Schulz, John F. Keaney Jr.

UMass Metabolic Network Publications

Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1alpha (PGC-1alpha) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1alpha in vascular function using mice with endothelial specific loss of function (PGC-1alpha EC KO) and endothelial specific gain of function (PGC-1alpha EC TG). Here we report that endothelial PGC-1alpha is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1alpha sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1alpha EC TG mice were ...


The Elasmobranch-Microbe Relationship: Trimethylamine N-Oxide Synthesis, Urea Hydrolysis, And Microbe-Osmolyte Interactions In The Atlantic Stingray, Dasyatis Sabina, Kaitlin Kelly Doucette Dec 2016

The Elasmobranch-Microbe Relationship: Trimethylamine N-Oxide Synthesis, Urea Hydrolysis, And Microbe-Osmolyte Interactions In The Atlantic Stingray, Dasyatis Sabina, Kaitlin Kelly Doucette

Master's Theses

The elasmobranch osmoregulatory strategy is predicated on the accumulation of nitrogenous compounds, primarily urea and trimethylamine n¬-oxide (TMAO). Despite the abundance of these plasma osmolytes, it is notable that elasmobranchs appear to lack urease and TMA oxidase (Tmase), enzymes that scavenge urea-nitrogen and synthesize TMAO, respectively. However, urease and Tmase are found in many species of bacteria. Therefore, I hypothesized that intestinal bacteria are responsible for urease and Tmase activity in elasmobranchs. Absent dietary nitrogen sources, I evaluated the effects of reduced intestinal microbiota on osmoregulation in Atlantic stingray (Dasyatis sabina) in vivo. D. sabina were given daily broad-spectrum ...


Cancer Metabolism: Fueling More Than Just Growth, Namgyu Lee, Dohoon Kim Dec 2016

Cancer Metabolism: Fueling More Than Just Growth, Namgyu Lee, Dohoon Kim

UMass Metabolic Network Publications

The early landmark discoveries in cancer metabolism research have uncovered metabolic processes that support rapid proliferation, such as aerobic glycolysis (Warburg effect), glutaminolysis, and increased nucleotide biosynthesis. However, there are limitations to the effectiveness of specifically targeting the metabolic processes which support rapid proliferation. First, as other normal proliferative tissues also share similar metabolic features, they may also be affected by such treatments. Secondly, targeting proliferative metabolism may only target the highly proliferating "bulk tumor" cells and not the slower-growing, clinically relevant cancer stem cell subpopulations which may be required for an effective cure. An emerging body of research indicates ...


Extracellular Matrix Remodeling And The Inflammatory Response During Skeletal Muscle Regeneration In Sarcopenic Obese Mice, Lemuel Arthur Brown Dec 2016

Extracellular Matrix Remodeling And The Inflammatory Response During Skeletal Muscle Regeneration In Sarcopenic Obese Mice, Lemuel Arthur Brown

Theses and Dissertations

AIM: Sarocpenic obesity is a national concern within the United States because this metabolic syndrome is tied with reduced mobility and quality of life. Both obesity and aging are associated with insulin-resistance, chronic low-grade inflammation and muscle weakness. Skeletal muscle regeneration is a process that involves the coordinated effort of myogenic regulatory factors (MRFs), inflammatory signaling, and extracellular matrix (ECM) remodeling for optimal regeneration. It has been demonstrated that obesity and aging have a reduction in muscle regeneration. It has not been examined if sarcopenic obesity will further reduce muscle mass and the regenerative process. The purpose of this study ...


Intraflagellar Transport Protein Ift20 Is Essential For Male Fertility And Spermiogenesis In Mice, Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E. Teves, Hong Liu, Jerome F. Strauss 3rd, Gregory J. Pazour, James A. Foster, Rex A. Hess, Zhibing Zhang Nov 2016

Intraflagellar Transport Protein Ift20 Is Essential For Male Fertility And Spermiogenesis In Mice, Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E. Teves, Hong Liu, Jerome F. Strauss 3rd, Gregory J. Pazour, James A. Foster, Rex A. Hess, Zhibing Zhang

University of Massachusetts Medical School Faculty Publications

Intraflagellar transport (IFT) is a conserved mechanism thought to be essential for the assembly and maintenance of cilia and flagella. However, little is known about its role in mammalian sperm flagella formation. To fill this gap, we disrupted the Ift20 gene in male germ cells. Homozygous mutant mice were infertile with significantly reduced sperm counts and motility. In addition, abnormally shaped elongating spermatid heads and bulbous round spermatids were found in the lumen of the seminiferous tubules. Electron microscopy revealed increased cytoplasmic vesicles, fiber-like structures, abnormal accumulation of mitochondria and a decrease in mature lysosomes. The few developed sperm had ...


Altered Interleukin-10 Signaling In Skeletal Muscle Regulates Obesity-Mediated Inflammation And Insulin Resistance, Sezin Dagdeviren, Dae Young Jung, Eunjung Lee, Randall H. Friedline, Hye Lim Noh, Jong Hun. Kim, Payal R. Patel, Nicholas Tsitsilianos, Andrew V. Tsitsilianos, Duy A. Tran, George H. Tsougranis, Caitlyn C. Kearns, Cecilia P. Uong, Jung Yeon. Kwon, Werner Muller, Ki Won. Lee, Jason K. Kim Nov 2016

Altered Interleukin-10 Signaling In Skeletal Muscle Regulates Obesity-Mediated Inflammation And Insulin Resistance, Sezin Dagdeviren, Dae Young Jung, Eunjung Lee, Randall H. Friedline, Hye Lim Noh, Jong Hun. Kim, Payal R. Patel, Nicholas Tsitsilianos, Andrew V. Tsitsilianos, Duy A. Tran, George H. Tsougranis, Caitlyn C. Kearns, Cecilia P. Uong, Jung Yeon. Kwon, Werner Muller, Ki Won. Lee, Jason K. Kim

University of Massachusetts Medical School Faculty Publications

Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (MIL10). After 16 weeks of a high-fat diet (HFD), MIL10 mice became markedly obese but showed improved insulin action compared to that of wild-type mice, which was largely due to increased glucose metabolism and reduced inflammation in skeletal muscle. Since leptin regulates inflammation, the beneficial effects of interleukin-10 (IL-10) were further examined in leptin-deficient ob/ob mice ...


Design Of Novel Ion Channel Modulators, Vladimir Yarov-Yarovoy Nov 2016

Design Of Novel Ion Channel Modulators, Vladimir Yarov-Yarovoy

Science Seminar Series

Function and modulation of neuronal sodium channels are critical for the neuromodulation of electrical excitability and synaptic transmission in neurons - the basis for many aspects of signal transduction, learning, memory and physiological regulation. Mutations in neuronal voltage-gated sodium channel genes are responsible for various human neurological disorders. Furthermore, human neuronal voltage-gated sodium channels are primary targets of therapeutic drugs used as local anesthetics and for treatment of neurological and cardiac disorders. Yarov-Yarovoy's lab is working on rational design of novel therapeutically useful blockers of voltage-gated sodium channels for treatment of pain and epilepsy. Serious, chronic pain affects at least ...


Structural And Genetic Analyses Of The Mycobacterium Tuberculosis Protein Kinase B Sensor Domain Identify A Potential Ligand-Binding Site, Daniil M. Prigozhin, Kadamba Papavinasasundaram, Christina E. Baer, Kenan C. Murphy, Alisa Moskaleva, Tony Y. Chen, Tom Alber, Christopher M. Sassetti Oct 2016

Structural And Genetic Analyses Of The Mycobacterium Tuberculosis Protein Kinase B Sensor Domain Identify A Potential Ligand-Binding Site, Daniil M. Prigozhin, Kadamba Papavinasasundaram, Christina E. Baer, Kenan C. Murphy, Alisa Moskaleva, Tony Y. Chen, Tom Alber, Christopher M. Sassetti

UMass Metabolic Network Publications

Monitoring the environment with serine/threonine protein kinases is critical for growth and survival of Mycobacterium tuberculosis, a devastating human pathogen. Protein kinase B (PknB) is a transmembrane serine/threonine protein kinase that acts as an essential regulator of mycobacterial growth and division. The PknB extracellular domain (ECD) consists of four repeats homologous to penicillin-binding protein and serine/threonine kinase associated (PASTA) domains, and binds fragments of peptidoglycan. These properties suggest that PknB activity is modulated by ECD binding to peptidoglycan substructures, however, the molecular mechanisms underpinning PknB regulation remain unclear. In this study, we report structural and genetic characterization ...


Cardiovascular Regulation By Kvβ1.1 Subunit, Jared Tur Oct 2016

Cardiovascular Regulation By Kvβ1.1 Subunit, Jared Tur

Graduate Theses and Dissertations

Heterologous expression systems such as COS-7 cells have demonstrated the profound effects of KCNAB1-3 or Kvβ1-3 proteins on voltage gated potassium channels (Kv) channels. Indeed, in the presence of these β-subunits transiently expressed Kv channels are often modulated in multiple ways. Kv channel membrane expression is often increased in the presence of β-subunits. In addition, non-inactivating Kv currents suddenly become fast-inactivating and fast-inactivating channels become even faster. While much research has demonstrated the profound effects the β-subunits in particular the Kvβ1 subunit have on transiently expressed Kv currents little to date is known of the physiological role it may play ...


A Gene-Centered C. Elegans Protein-Dna Interaction Network Provides A Framework For Functional Predictions, Juan Fuxman Bass, Carles Pons, Lucie Kozlowski, John S. Reece-Hoyes, Shaleen Shrestha, Amy D. Holdorf, Akihiro Mori, Chad L. Myers, Albertha J. M. Walhout Oct 2016

A Gene-Centered C. Elegans Protein-Dna Interaction Network Provides A Framework For Functional Predictions, Juan Fuxman Bass, Carles Pons, Lucie Kozlowski, John S. Reece-Hoyes, Shaleen Shrestha, Amy D. Holdorf, Akihiro Mori, Chad L. Myers, Albertha J. M. Walhout

Open Access Articles

Transcription factors (TFs) play a central role in controlling spatiotemporal gene expression and the response to environmental cues. A comprehensive understanding of gene regulation requires integrating physical protein-DNA interactions (PDIs) with TF regulatory activity, expression patterns, and phenotypic data. Although great progress has been made in mapping PDIs using chromatin immunoprecipitation, these studies have only characterized ~10% of TFs in any metazoan species. The nematode C. elegans has been widely used to study gene regulation due to its compact genome with short regulatory sequences. Here, we delineated the largest gene-centered metazoan PDI network to date by examining interactions between 90 ...


Mtorc2 Promotes Lipid Storage And Suppresses Thermogenesis In Brown Adipose Tissue In Part Through Akt-Independent Regulation Of Foxo1: A Dissertation, Chien-Min Hung Oct 2016

Mtorc2 Promotes Lipid Storage And Suppresses Thermogenesis In Brown Adipose Tissue In Part Through Akt-Independent Regulation Of Foxo1: A Dissertation, Chien-Min Hung

GSBS Dissertations and Theses

Recent studies suggest adipose tissue plays a critical role in regulating whole body energy homeostasis in both animals and humans. In particular, activating brown adipose tissue (BAT) activity is now appreciated as a potential therapeutic strategy against obesity and metabolic disease. However, the signaling circuits that coordinate nutrient uptake and BAT function are poorly understood. Here, I investigated the role of the nutrient-sensing mTOR signaling pathway in BAT by conditionally deleting Rictor, which encodes an essential component of mTOR Complex 2 (mTORC2) either in brown adipocyte precursors or mature brown adipocytes. In general, inhibiting BAT mTORC2 reduces glucose uptake and ...


Cxcr4 Identifies Transitional Bone Marrow Premonocytes That Replenish The Mature Monocyte Pool For Peripheral Responses, Shu Zhen Chong, Maximilien Evrard, John E. Harris, Lai Guan Ng Oct 2016

Cxcr4 Identifies Transitional Bone Marrow Premonocytes That Replenish The Mature Monocyte Pool For Peripheral Responses, Shu Zhen Chong, Maximilien Evrard, John E. Harris, Lai Guan Ng

UMass Metabolic Network Publications

It is well established that Ly6Chi monocytes develop from common monocyte progenitors (cMoPs) and reside in the bone marrow (BM) until they are mobilized into the circulation. In our study, we found that BM Ly6Chi monocytes are not a homogenous population, as current data would suggest. Using computational analysis approaches to interpret multidimensional datasets, we demonstrate that BM Ly6Chi monocytes consist of two distinct subpopulations (CXCR4hi and CXCR4lo subpopulations) in both mice and humans. Transcriptome studies and in vivo assays revealed functional differences between the two subpopulations. Notably, the CXCR4hi subset proliferates and is immobilized in the BM for the ...


Cxcr4 Identifies Transitional Bone Marrow Premonocytes That Replenish The Mature Monocyte Pool For Peripheral Responses, Shu Zhen Chong, John E. Harris, Lai Guan Ng Oct 2016

Cxcr4 Identifies Transitional Bone Marrow Premonocytes That Replenish The Mature Monocyte Pool For Peripheral Responses, Shu Zhen Chong, John E. Harris, Lai Guan Ng

UMass Metabolic Network Publications

It is well established that Ly6Chi monocytes develop from common monocyte progenitors (cMoPs) and reside in the bone marrow (BM) until they are mobilized into the circulation. In our study, we found that BM Ly6Chi monocytes are not a homogenous population, as current data would suggest. Using computational analysis approaches to interpret multidimensional datasets, we demonstrate that BM Ly6Chi monocytes consist of two distinct subpopulations (CXCR4hi and CXCR4lo subpopulations) in both mice and humans. Transcriptome studies and in vivo assays revealed functional differences between the two subpopulations. Notably, the CXCR4hi subset proliferates and is immobilized in the BM for the ...


Maintenance Of The Ph Gradient In The Gastric Mucus Layer., Owen Lewis Oct 2016

Maintenance Of The Ph Gradient In The Gastric Mucus Layer., Owen Lewis

Annual Symposium on Biomathematics and Ecology: Education and Research

No abstract provided.


The Rna-Binding Protein Atx-2 Regulates Cytokinesis Through Par-5 And Zen-4, Megan M. Gnazzo, Eva-Maria E. Uhlemann, Alex R. Villarreal, Masaki Shirayama, Eddie G. Dominguez, Ahna R. Skop Oct 2016

The Rna-Binding Protein Atx-2 Regulates Cytokinesis Through Par-5 And Zen-4, Megan M. Gnazzo, Eva-Maria E. Uhlemann, Alex R. Villarreal, Masaki Shirayama, Eddie G. Dominguez, Ahna R. Skop

Open Access Articles

The spindle midzone harbors both microtubules and proteins necessary for furrow formation and the completion of cytokinesis. However, the mechanisms that mediate the temporal and spatial recruitment of cell division factors to the spindle midzone and midbody remain unclear. Here we describe a mechanism governed by the conserved RNA-binding protein ATX-2/Ataxin-2, which targets and maintains ZEN-4 at the spindle midzone. ATX-2 does this by regulating the amount of PAR-5 at mitotic structures, particularly the spindle, centrosomes, and midbody. Preventing ATX-2 function leads to elevated levels of PAR-5, enhanced chromatin and centrosome localization of PAR-5-GFP, and ultimately a reduction of ...


Adipocyte-Specific Hypoxia-Inducible Gene 2 Promotes Fat Deposition And Diet-Induced Insulin Resistance, Marina Distefano, Rachel J. Roth Flach, Ozlem Senol-Cosar, Laura V. Danai, Joseph V. Virbasius, Sarah M. Nicoloro, Juerg R. Straubhaar, Sezin Dagdeviren, Martin Wabitsch, Olga T. Gupta, Jason K. Kim, Michael P. Czech Sep 2016

Adipocyte-Specific Hypoxia-Inducible Gene 2 Promotes Fat Deposition And Diet-Induced Insulin Resistance, Marina Distefano, Rachel J. Roth Flach, Ozlem Senol-Cosar, Laura V. Danai, Joseph V. Virbasius, Sarah M. Nicoloro, Juerg R. Straubhaar, Sezin Dagdeviren, Martin Wabitsch, Olga T. Gupta, Jason K. Kim, Michael P. Czech

Open Access Articles

OBJECTIVE: Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis.

METHOD: White and brown adipocyte-deficient (Hig2fl/fl x Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl x Ucp1 cre+) mice were generated to investigate the role of Hig2 in ...


An Alternative Splicing Program Promotes Adipose Tissue Thermogenesis, Santiago Vernia, Yvonne J. K. Edwards, Myoung Souk Han, Julie Cavanagh-Kyros, Tamera Barrett, Jason K. Kim, Roger J. Davis Sep 2016

An Alternative Splicing Program Promotes Adipose Tissue Thermogenesis, Santiago Vernia, Yvonne J. K. Edwards, Myoung Souk Han, Julie Cavanagh-Kyros, Tamera Barrett, Jason K. Kim, Roger J. Davis

University of Massachusetts Medical School Faculty Publications

Alternative pre-mRNA splicing expands the complexity of the transcriptome and controls isoform-specific gene expression. Whether alternative splicing contributes to metabolic regulation is largely unknown. Here we investigated the contribution of alternative splicing to the development of diet-induced obesity. We found that obesity-induced changes in adipocyte gene expression include alternative pre-mRNA splicing. Bioinformatics analysis associated part of this alternative splicing program with sequence specific NOVA splicing factors. This conclusion was confirmed by studies of mice with NOVA deficiency in adipocytes. Phenotypic analysis of the NOVA-deficient mice demonstrated increased adipose tissue thermogenesis and improved glycemia. We show that NOVA proteins mediate a ...


Viral Proteases As Drug Targets And The Mechanisms Of Drug Resistance: A Dissertation, Kuan-Hung Lin Sep 2016

Viral Proteases As Drug Targets And The Mechanisms Of Drug Resistance: A Dissertation, Kuan-Hung Lin

GSBS Dissertations and Theses

Viral proteases have been shown to be effective targets of anti-viral therapies for human immunodeficiency virus (HIV) and hepatitis C virus (HCV). However, under the pressure of therapy including protease inhibitors, the virus evolves to select drug resistance mutations both in the protease and substrates. In my thesis study, I aimed to understand the mechanisms of how this protease−substrate co-evolution contributes to drug resistance. Currently, there are no approved drugs against dengue virus (DENV); I investigated substrate recognition by DENV protease and designed cyclic peptides as inhibitors targeting the prime site of dengue protease.

First, I used X-ray crystallography ...


Cal And Magi Pdz Protein Regulation Of Crfr1 And 5-Ht2ar Trafficking And Signaling, Maha Mahmoud Hammad Aug 2016

Cal And Magi Pdz Protein Regulation Of Crfr1 And 5-Ht2ar Trafficking And Signaling, Maha Mahmoud Hammad

Electronic Thesis and Dissertation Repository

PDZ (PSD95/Disc Large/Zona Occludens) domain-containing proteins are scaffolding proteins that play important roles in regulating the activity of G protein-coupled receptors. Corticotropin Releasing Factor Receptor 1 (CRFR1) and Serotonin 2A Receptor (5-HT2AR) are two GPCRs that are commonly associated with mental disorders. Both receptors also contain a class I PDZ-binding motif at the carboxyl terminal tail. In the first chapter, we investigate the effects of CAL (CFTR-associated ligand) on regulating the trafficking and signaling of CRFR1. We demonstrate a role for CAL in inhibiting CRFR1 endocytosis, cell surface expression, and CRF-mediated ERK1/2 signaling via the ...


Suppression Of Ischemia In Arterial Occlusive Disease By Jnk-Promoted Native Collateral Artery Development, Kasmir Ramo, Koichi Sugamura, Siobhan M. Craige, John F. Keaney Jr., Roger J. Davis Aug 2016

Suppression Of Ischemia In Arterial Occlusive Disease By Jnk-Promoted Native Collateral Artery Development, Kasmir Ramo, Koichi Sugamura, Siobhan M. Craige, John F. Keaney Jr., Roger J. Davis

Davis Lab Publications

Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. We report that disruption of the mixed-lineage protein kinase (MLK) - cJun NH2-terminal kinase (JNK) signaling pathway in endothelial cells causes severe blockade of blood flow and failure to recover in the murine femoral artery ligation model of hindlimb ischemia. We show that the MLK-JNK pathway is required for the formation of native collateral arteries that can restore circulation following arterial occlusion. Disruption of the MLK-JNK pathway causes decreased Dll4/Notch signaling, excessive ...


Advances In Gene Therapy For Diseases Of The Eye, Lolita Petit, Hemant Khanna, Claudio Punzo Aug 2016

Advances In Gene Therapy For Diseases Of The Eye, Lolita Petit, Hemant Khanna, Claudio Punzo

UMass Metabolic Network Publications

Over the last few years, huge progress has been made with regard to the understanding of molecular mechanisms underlying the pathogenesis of neurodegenerative diseases of the eye. Such knowledge has led to the development of gene therapy approaches to treat these devastating disorders. Challenges regarding the efficacy and efficiency of therapeutic gene delivery have driven the development of novel therapeutic approaches, which continue to evolve the field of ocular gene therapy. In this review article, we will discuss the evolution of preclinical and clinical strategies that have improved gene therapy in the eye, showing that treatment of vision loss has ...


Intestinal Cytoplasmic Lipid Droplets, Associated Proteins, And The Regulation Of Dietary Fat Absorption, Theresa M. D'Aquila Aug 2016

Intestinal Cytoplasmic Lipid Droplets, Associated Proteins, And The Regulation Of Dietary Fat Absorption, Theresa M. D'Aquila

Open Access Dissertations

Dietary fat provides essential nutrients, contributes to energy balance, and regulates blood lipid concentrations. These functions are important to health, but can also become dysregulated and contribute to diseases such as obesity, diabetes, and cardiovascular disease. The small intestine absorbs dietary fat through an efficient multi step process of digestion, uptake, metabolism, and secretion or storage. When dietary fat is taken up by the absorptive cells of the small intestine, enterocytes, it can be secreted into circulation where it contributes to blood lipid levels or temporarily stored in cytoplasmic lipid droplets (CLDs). The objective of this dissertation is to investigate ...


Exploring The Relationship Between Behaviour And Neurochemistry In The Polyphenic Spider, Anelosimus Studiosus (Araneae: Theridiidae), Jennifer B. Price Aug 2016

Exploring The Relationship Between Behaviour And Neurochemistry In The Polyphenic Spider, Anelosimus Studiosus (Araneae: Theridiidae), Jennifer B. Price

Electronic Theses and Dissertations

The importance of social behaviour is evident in human society, but there are both costs and benefits associated with cooperation and sociality throughout the animal kingdom. At what point do the benefits outweigh the costs, and when do selective pressures favour sociality and colonization over solitude and independence? To investigate these questions, we have focused on an anomalous species of spider, Anelosimus studiosus, also known now as the northern social spider. Throughout its broad range, A. studiosus is solitary and aggressive, but recently, colonies of cooperative and social individuals have been observed at northern latitudes. This leads to two research ...


Protein Kinase Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (Map4k4) Promotes Obesity-Induced Hyperinsulinemia, Rachel J. Roth Flach, Laura V. Danai, Marina Distefano, Mark Kelly, Lorena Garcia Menendez, Agata Jurczyk, Rohit B. Sharma, Dae Young Jung, Jong Hun Kim, Jason K. Kim, Rita Bortell, Laura C. Alonso, Michael P. Czech Jul 2016

Protein Kinase Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (Map4k4) Promotes Obesity-Induced Hyperinsulinemia, Rachel J. Roth Flach, Laura V. Danai, Marina Distefano, Mark Kelly, Lorena Garcia Menendez, Agata Jurczyk, Rohit B. Sharma, Dae Young Jung, Jong Hun Kim, Jason K. Kim, Rita Bortell, Laura C. Alonso, Michael P. Czech

Open Access Articles

Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced beta cell mass, fewer proliferating beta cells and reduced islet-specific gene mRNA expression compared ...


Dietary Weight Loss Advice In Us Health Magazines And Its Relation To Ancestral Diet, Risa J. Stein, Marium A. Choudhry, Thomas J. Murray Jr. Jul 2016

Dietary Weight Loss Advice In Us Health Magazines And Its Relation To Ancestral Diet, Risa J. Stein, Marium A. Choudhry, Thomas J. Murray Jr.

Journal of Evolution and Health

As rates of overweight and obesity have risen in the US, the public has sought effective strategies for weight loss through dietary modification. A proliferation of processed foods and changing governmental nutrition guidelines have both impacted dietary intake patterns. While physicians are considered respectable sources of weight-loss information, increasingly the public has turned to the media, particularly magazines, for weight loss advice. This study investigated the dietary recommendations found in the five leading US health-related magazines and compared those recommendations to ancestral diets. With a couple notable exceptions, leading health magazines present consistent recommendations for dietary modifications to promote weight ...


Isothermal Titration Calorimetry Uncovers Substrate Promiscuity Of Bicupin Oxalate Oxidase From Ceriporiopsis Subvermispora, Hassan Rana, Patricia Moussatche, Lis Souza Rocha, Ellen W. Moomaw Jun 2016

Isothermal Titration Calorimetry Uncovers Substrate Promiscuity Of Bicupin Oxalate Oxidase From Ceriporiopsis Subvermispora, Hassan Rana, Patricia Moussatche, Lis Souza Rocha, Ellen W. Moomaw

Ellen Moomaw

Isothermal titration calorimetry (ITC) may be used to determine the kinetic parameters of enzymecatalyzed reactions when neither products nor reactants are spectrophotometrically visible and when the reaction products are unknown. We report here the use of the multiple injection method of ITC to characterize the catalytic properties of oxalate oxidase (OxOx) from Ceriporiopsis subvermispora (CsOxOx), a manganese dependent enzyme that catalyzes the oxygen-dependent oxidation of oxalate to carbon dioxide in a reaction coupled with the formation of hydrogen peroxide. CsOxOx is the first bicupin enzyme identified that catalyzes this reaction. The multiple injection ITC method of measuring OxOx activity involves ...


Isothermal Titration Calorimetry Uncovers Substrate Promiscuity Of Bicupin Oxalate Oxidase From Ceriporiopsis Subvermispora, Hassan Rana, Patricia Moussatche, Lis Souza Rocha, Ellen W. Moomaw Jun 2016

Isothermal Titration Calorimetry Uncovers Substrate Promiscuity Of Bicupin Oxalate Oxidase From Ceriporiopsis Subvermispora, Hassan Rana, Patricia Moussatche, Lis Souza Rocha, Ellen W. Moomaw

Ellen Moomaw

Isothermal titration calorimetry (ITC) may be used to determine the kinetic parameters of enzymecatalyzed reactions when neither products nor reactants are spectrophotometrically visible and when the reaction products are unknown. We report here the use of the multiple injection method of ITC to characterize the catalytic properties of oxalate oxidase (OxOx) from Ceriporiopsis subvermispora (CsOxOx), a manganese dependent enzyme that catalyzes the oxygen-dependent oxidation of oxalate to carbon dioxide in a reaction coupled with the formation of hydrogen peroxide. CsOxOx is the first bicupin enzyme identified that catalyzes this reaction. The multiple injection ITC method of measuring OxOx activity involves ...