Translational Medical Research Commons^™

Nucleus Accumbens Deep Brain Stimulation In A Rat Model Of Binge Eating, W. T. Doucette, J. Y. Khokhar, A. I. Green

Dartmouth Scholarship

Binge eating (BE) is a difficult-to-treat behavior with high relapse rates, thus complicating several disorders including obesity. In this study, we tested the effects of high-frequency deep brain stimulation (DBS) in a rodent model of BE. We hypothesized that BE rats receiving high-frequency DBS in the nucleus accumbens (NAc) core would have reduced binge sizes compared with sham stimulation in both a 'chronic BE' model as well as in a 'relapse to chronic BE' model. Male Sprague-Dawley rats (N=18) were implanted with stimulating electrodes in bilateral NAc core, and they received either active stimulation (N=12) or sham stimulation (N=6) for …

Hdac6 Activity Is A Non-Oncogene Addiction Hub For Inflammatory Breast Cancers, Preeti Putcha, Jiyang Yu, Ruth Rodriguez-Barrueco, Laura Saucedo-Cuevas, Patricia Villagrasa, Eva Murga-Penas, Steven N. Quayle, Min Yang, Veronica Castro, David Llobet-Navas, Daniel Birbaum, Pascal Finetti, Wendy A. Woodward, Francois Bertucci, Mary Alpaugh, Andrea Califano, Jose Silva

Faculty Scholarship for the College of Science & Mathematics

Inflammatory breast cancer (IBC) is the most lethal form of breast cancers with a 5-year survival rate of only 40 %. Despite its lethality, IBC remains poorly understood which has greatly limited its therapeutic management. We thus decided to utilize an integrative functional genomic strategy to identify the Achilles’ heel of IBC cells.

Impact Of Sleep And Circadian Disruption On Energy Balance And Diabetes: A Summary Of Workshop Discussions, Deanna M. Arble, Joseph Bass, Cecilia Diniz Behn, Matthew P. Butler, Etienne Challet, Charles Czeisler, Christopher M. Depner, Joel Elmquist, Paul Franken, Michael A. Grandner, Erin C. Hanlon, Alex C. Keene, Michael J. Joyner, Ilia Karatsoreos, Philip A. Kern, Samuel Klein, Christopher J. Morris, Allan I. Pack, Satchidananda Panda, Louis J. Ptacek, Naresh M. Punjabi, Paolo Sassone-Corsi, Frank A. Scheer, Richa Saxena, Elizabeth R. Seaquest, Matthew S. Thimgan, Eve Van Cauter, Kenneth P. Wright

Clinical and Translational Science Faculty Publications

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact …

Fibronectin Signals Through Integrin Α5Β1 To Regulate Cardiovascular Development In A Cell Type-Specific Manner., Dongying Chen, Xia Wang, Dong Liang, Julie Gordon, Ashok Mittal, Nancy Manley, Karl Degenhardt, Sophie Astrof

Department of Medicine Faculty Papers

Fibronectin (Fn1) is an evolutionarily conserved extracellular matrix glycoprotein essential for embryonic development. Global deletion of Fn1 leads to mid-gestation lethality from cardiovascular defects. However, severe morphogenetic defects that occur early in embryogenesis in these embryos precluded assigning a direct role for Fn1 in cardiovascular development. We noticed that Fn1 is expressed in strikingly non-uniform patterns during mouse embryogenesis, and that its expression is particularly enriched in the pharyngeal region corresponding with the pharyngeal arches 3, 4, and 6. This region bears a special importance for the developing cardiovascular system, and we hypothesized that the localized enrichment of Fn1 in …

Breast Cancer-Derived Extracellular Vesicles: Characterization And Contribution To The Metastatic Phenotype, Toni M. Green, Mary L. Alpaugh, Sanford H. Barsky, Germana Rappa, Aurelio Lorico

Faculty Scholarship for the College of Science & Mathematics

The study of extracellular vesicles (EVs) in cancer progression is a complex and rapidly evolving field. Whole categories of cellular interactions in cancer which were originally presumed to be due solely to soluble secreted molecules have now evolved to include membrane-enclosed extracellular vesicles (EVs), which include both exosomes and shed microvesicles (MVs), and can contain many of the same molecules as those secreted in soluble form but many different molecules as well. EVs released by cancer cells can transfer mRNA, miRNA, and proteins to different recipient cells within the tumor microenvironment, in both an autocrine and paracrine manner, causing a …

Akt Kinase C-Terminal Modifications Control Activation Loop Dephosphorylation And Enhance Insulin Response., Tung O. Chan, Jin Zhang, Brian C. Tiegs, Brian Blumhof, Linda Yan, Nikhil Keny, Morgan Penny, Xue Li, John M. Pascal, Roger S. Armen, Ulrich Rodeck, Raymond B. Penn

Center for Translational Medicine Faculty Papers

The Akt protein kinase, also known as protein kinase B, plays key roles in insulin receptor signalling and regulates cell growth, survival and metabolism. Recently, we described a mechanism to enhance Akt phosphorylation that restricts access of cellular phosphatases to the Akt activation loop (Thr(308) in Akt1 or protein kinase B isoform alpha) in an ATP-dependent manner. In the present paper, we describe a distinct mechanism to control Thr(308) dephosphorylation and thus Akt deactivation that depends on intramolecular interactions of Akt C-terminal sequences with its kinase domain. Modifications of amino acids surrounding the Akt1 C-terminal mTORC2 (mammalian target of rapamycin …

Isoform-Specific Dynamic Translocation Of Pkc By Α1-Adrenoceptor Stimulation In Live Cells., Jin O-Uchi, Jaime Sorenson, Bong Sook Jhun, Jyotsna Mishra, Stephen Hurst, Kaleef Williams, Shey-Shing Sheu, Coeli M.B. Lopes

Center for Translational Medicine Faculty Papers

Protein kinase C (PKC) plays key roles in the regulation of signal transduction and cellular function in various cell types. At least ten PKC isoforms have been identified and intracellular localization and trafficking of these individual isoforms are important for regulation of enzyme activity and substrate specificity. PKC can be activated downstream of Gq-protein coupled receptor (GqPCR) signaling and translocate to various cellular compartments including plasma membrane (PM). Recent reports suggested that different types of GqPCRs would activate different PKC isoforms (classic, novel and atypical PKCs) with different trafficking patterns. However, the knowledge of isoform-specific activation of PKC by each …

A Randomized Controlled Trial Of Exercise In Spinal And Bulbar Muscular Atrophy., Joseph A Shrader, Ilona Kats, Angela Kokkinis, Cris Zampieri, Ellen Levy, Galen O Joe, Joshua G. Woolstenhulme, Bart E Drinkard, Michaele R Smith, Willie Ching, Laboni Ghosh, Derrick Fox, Sungyoung Auh, Alice B Schindler, Kenneth H Fischbeck, Christopher Grunseich

Physical Therapy and Health Care Sciences Faculty Publications

OBJECTIVE: To determine the safety and efficacy of a home-based functional exercise program in spinal and bulbar muscular atrophy (SBMA).

METHODS: Subjects were randomly assigned to participate in 12 weeks of either functional exercises (intervention) or a stretching program (control) at the National Institutes of Health in Bethesda, MD. A total of 54 subjects enrolled, and 50 completed the study with 24 in the functional exercise group and 26 in the stretching control group. The primary outcome measure was the Adult Myopathy Assessment Tool (AMAT) total score, and secondary measures included total activity by accelerometry, muscle strength, balance, timed up …

Insulin-Resistant Subjects Have Normal Angiogenic Response To Aerobic Exercise Training In Skeletal Muscle, But Not In Adipose Tissue, R. Grace Walton, Brian S. Finlin, Jyothi Mula, Douglas E. Long, Beibei Zhu, Christopher S. Fry, Philip M. Westgate, Jonah D. Lee, Tamara Bennett, Philip A. Kern, Charlotte A. Peterson

Clinical and Translational Science Faculty Publications

Reduced vessel density in adipose tissue and skeletal muscle is associated with obesity and may result in decreased perfusion, decreased oxygen consumption, and insulin resistance. In the presence of VEGFA, Angiopoietin-2 (Angpt2) and Angiopoietin-1 (Angpt1) are central determinants of angiogenesis, with greater Angpt2:Angpt1 ratios promoting angiogenesis. In skeletal muscle, exercise training stimulates angiogenesis and modulates transcription of VEGFA, Angpt1, and Angpt 2. However, it remains unknown whether exercise training stimulates vessel growth in human adipose tissue, and it remains unknown whether adipose angiogenesis is mediated by angiopoietin signaling. We sought to determine whether insulin-resistant subjects would display an impaired angiogenic …

New Functions For Alpha-Catenins In Health And Disease: From Cancer To Heart Regeneration., Alexia Vite, Jifen Li, Glenn L. Radice

Center for Translational Medicine Faculty Papers

Strong cell-cell adhesion mediated by adherens junctions is dependent on anchoring the transmembrane cadherin molecule to the underlying actin cytoskeleton. To do this, the cadherin cytoplasmic domain interacts with catenin proteins, which include α-catenin that binds directly to filamentous actin. Originally thought to be a static structure, the connection between the cadherin/catenin adhesion complex and the actin cytoskeleton is now considered to be dynamic and responsive to both intercellular and intracellular signals. Alpha-catenins are mechanosensing proteins that undergo conformational change in response to cytoskeletal tension thus modifying the linkage between the cadherin and the actin cytoskeleton. There are three α-catenin …

Increasing Adipocyte Lipoprotein Lipase Improves Glucose Metabolism In High Fat Diet-Induced Obesity, R. Grace Walton, Beibei Zhu, Resat Unal, Michael Spencer, Manjula Sunkara, Andrew J. Morris, Richard Charnigo, Wendy Katz, Alan Daugherty, Deborah A. Howatt, Philip A. Kern, Brian S. Finlin

Clinical and Translational Science Faculty Publications

Background: Lipoprotein lipase regulates fat uptake into adipose tissue.

Results: A mouse model with increased adipose tissue lipoprotein lipase has improved glucose metabolism when challenged with a high fat diet.

Conclusion: Increasing adipose tissue lipoprotein lipase improves adipose tissue function.

Significance: Adipose tissue lipoprotein lipase protects against obesity-induced glucose and insulin intolerance.

Vestibular Dysfunction, Altered Macular Structure And Trait Localization In A/J Inbred Mice, Sarath Vijayakumar, Teresa E. Lever, Jessica Pierce, Xing Zhao, David Bergstrom, Yunxia Wang Lundberg, Timothy A. Jones, Sherri M. Jones

Department of Special Education and Communication Disorders: Faculty Publications

A/J mice develop progressive hearing loss that begins before one month of age and is attributed to cochlear hair cell degeneration. Screening tests indicated this strain also develops early onset vestibular dysfunction and has otoconial deficits. The purpose of this study was to characterize the vestibular dysfunction and macular structural pathology over the lifespan of A/J mice. Vestibular function was measured using linear vestibular evoked potentials (VsEPs). Macular structural pathology was evaluated using light microscopy, SEM, TEM, confocal microscopy and Western blotting. Individually, vestibular functional deficits in mice ranged from mild to profound. On average, A/J mice had significantly reduced …

Brain Blast 2015 Speakers Poster, Annie Leslie

Brain Blast

Poster from UNE's Brain Blast 2015 listing the expected presenters at this event.*

The Role Of Mmp9 In Satellite Cell Activation After Increased Activity, Mike H.M.H. Pang, Jung A. Kim, Gary E. Mccall, Ryan S. Mehan, J-P Hyatt

Summer Research

The unique adaptive ability of skeletal muscle to meet functional demands is exemplified in its response to exercise. Though little is known about the molecular mechanisms that regulate this plasticity, the extracellular matrix (ECM) is believed to play a large role. The basal lamina is a specialized layer of ECM that lies in direct contact with the cell membrane of muscle fibers and facilitates environment-to-cell interactions. Matrix metalloproteinase-9 (MMP-9) is an enzyme in the basal lamina that regulates much of these adaptive processes. During exercise, the regenerative process of damaged tissue requires the activation of muscle-specific stem cells known as …