Novel Signal Transduction Therapeutic Strategies for Paralysis and Pain After Spinal Cord Injury (SCI)
|
|
|
- Grant White
- 6 years ago
- Views:
Transcription
1 Novel Signal Transduction Therapeutic Strategies for Paralysis and Pain After Spinal Cord Injury (SCI) Chen Guang Yu, PhD, MD Assistant Professor Spinal Cord and Brain Injury Research Center Department of Anatomy and Neurobiology University of Kentucky College of Medicine Lexington, KY, USA 1
2 OUTLINE (Therapeutic Strategies) 1 Targeting Individual ERK Isoform and Its Cross-talk with Calpain 1 for Neuroprotection 2 FluBZ Therapy Targeting Multiple Signal Pathways for SCI 2
3 Traumatic Spinal Cord Injury (SCI) Permanent locomotor disability 11, new cases occur each year in USA Over 25 million SCI patients with paralysis in the world SCI-pain (a common complication, 7-9%) refractory to conventional analgesic treatment Sustained activation of multiple signal pathways after SCI Activation of the ERK1/2 signaling cascade by excitotoxic spinal cord injury Yu CG, Yezierski RP 25 Calpain in the CNS: from synaptic function to neurotoxicity Liu J, Liu MC, Wang KK 28 Cell cycle activation and spinal cord injury Wu J, Stoica BA, Faden AI 211 No effective treatments for Paralysis and Pain after SCI Yu, et al, 25, 21; Crown et al, 26; Zhao et al, 27, We, et al 211 3
4 Part 1: Targeting Individual ERK and Its Cross-talk with Calpain 1 for Treating paralysis and SCI-pain Eur J Biochem (Review) 271, (24) Role of ERK 1 and 2 in neuronal survival Michal Hetman1,2,3 and Agata Gozdz1 J Pharmacol Exp Ther (Review) 26 Dec;319(3):991-7 A death-promoting role for ERK1/2 Zhuang S, Schnellmann RG Hypothesis: reducing ERK2, while sparing ERK1, protects against SCI ERK2 shrna sequence sense loop antisense 5 -CACCGCACCTCAGCAATGATCATCGAAATGATCATTGCTGAGGTGC-3 BamHI XbaI 5 -LTR RRE U6 DNA Flap shrna CMV EGFP WPRE 3 LTR Lentiviral ERK2 shrna-gfp vector construction and production 4
5 The role of ERK2 in locomotor function after SCI Locomotor function Test Spinal ERK2 Knockdown At 2 wks post-injury in rats ERK1 44 kda ERK2 42 kda Viral titer: 5X1 7 to 1X1 8 BBB Score LV-Control LV-ERK2 shrna * * * * pre T1 23 kdyn IH SCI Device L-E Rats n=7/group Days Post-injury Eriochrome cyanine (EC) stained spinal sections Tissue Sparing Assessment I II 6 3 Epicenter 3 6 Rostral Distance from epicenter (mm) Caudal I: LV-ERK2 shrna; II: LV-Control 3 Total Tissue Sparing (mm ) LV-Control Yu et al, J Neurochemistry 21 * LV-ERK2 shrna 5
6 Contributions of ERK1/2 to pain behaviors after excitotoxic SCI QUIS: Quisqualic acid an AMPA receptor agonist ERK1/2 activation after Excitotoxic SCI Saline QUIS Phospho ERK 44 Kda (ERK1) 42 Kda (ERK2) Total ERK 44 Kda (ERK1) 42 Kda (ERK2) Self-injurious over-grooming of the affected dermatome Group n Grooming Behavior Incidence PD % Vehicle % (PD µg/15µl delivered to surface of the cord For 1 h pre and immediately post-injection of QUIS) perk2, but not perk1, contributes to the complete Freund s Adjvant-induced and formalin-induced pain (Xu Q, et al, 28; Alter BJ et al, 21) 6
7 Determination of targets of ERK1/2 activation after SCI ERK1/2 inhibition (U126) down-regulates calpain 1 expression 4h after SCI in rats 3 ** 25 Calpain 1 GAPDH Calpain 1 GAPDH SCI+ U126 iv SCI+ U126 ip SCI+ Vehicle Sham 76 KDa 36 KDa 76 KDa 36 KDa Calpa ain-1 Protein level (Calp pain-1/gapdh) # # SCI+U126-IV (n=4) SCI+U126-IP (n=4) SCI+Vehicle (n=4) sham (n=4) U126 iv (2mg/kg) and ip (1mg/kg) pretreatment 7
8 Role of calpain 1 in SCI Spinal CAPN1 knockdown At 2 wks post-injury in rats Locomotor Function Test T1 18 kdyn IH SCI Device L-E Rats Viral titer: 5X1 7 to 1X1 8 I: LV-Control shrna II: LV-CAPN1 shrna (Scale bar: 1 μm) a b c d e f g h i j k 4 mm 2 mm 1 mm Lesion epicenter 1 mm 2 mm 4 mm Rostral Tissue Sparing Assessment l m n Caudal Eriochrome cyanine (EC) staining I II Total Tissue Sparing (mm 3 ) * LV-calpain 1 shrna LV-control Yu et al, Journal Neurotrauma, 212 n=1 per group, ANOVA followed by the Bonferroni post hoc test 8
9 Determination of CAPN1 targets Using cocktail antibodies WT-Sham WT-SCI 6h CAPN1 KO SCI 6h Phospho-SHP2 (72 kda) Phospho-AKT (6 kda) Phospho-p44/p42 ERK1/2 (44 kda and 42 kda) eif4e (25 kda, loading control protein) CAPN1 deletion increased ERK1/2 activation after acute SCI in mice
10 CAPN1 deletion exacerbated SCI-pain after acute SCI in mice CAPN1 deletion showed earlier onset of grooming Onset of Grooming (Days) WT CAPN1 KO ** CAPN1 deletion worsened SCI-pain after SCI in mice Severity of Grooming WT CAPN1 KO CAPN1 deletion exacerbated SCI-pain after SCI in mice Group n Grooming Behavior Incidence Onset CAPN-KO 5 4 8% 6 WT % 125 1
11 Summary for Part 1: Targeting calpain 1 and ERK2 Cross-talk may provide synergistic effects after SCI CAPN1reduction or deletion ERK1 Activation ERK2 Activation ERK2 Inhibition Spared ERK1 Neuroprotective Neuroprotective Improves Locomotion Worsens SCI-Pain Improves locomotion Reduces pain ERK1-/- mice exhibit exacerbated paralysis in EAE (Agrawal A, 26) ERK1 plays a critical protective role against NMDA injury (Nakazawa T, 28) 11
12 Part 2: FBZ/FluBZ Therapy Targeting Multiple Signal Pathways for SCI Fenbendazole (FBZ) A benzimidazole anthelminth for animal use only FBZ inhibits microtubule formations, and thereby blocking mitosis in nematodes FBZ has greater sensitivity for nematodes as compared to mammalian tubulin Its influence on the outcomes of ongoing experiments are a concern Villar et al, 27; Friedman et al,
13 FBZ improves locomotor function and tissue sparing after moderate SCI in mice Locomotor Function T9 5 kdyn IH SCI Device C57BL/6 mice Tissue Sparing Eriochrome cyanine (EC) staining for myelin Yu CG et al, 214 FBZ-medicated feed (8 mg/kg/day) for 4 wks prior to SCI, n=7/group 13
14 FluBZ improved locomotor function And tissue sparing after SCI in rats Approved for human use, Long term treatment without adverse effects Total Tissue Sparing Locomotor Function T1 18 kdyn IH SCI Device SD rats SCI+Vehicle SCIFluBZ+ Total Tissue Sparing White Matter Sparing Gray Matter Sparing Total Tissue Sparing (mm 3 ) *** SCI-FluBZ SCI-Vehicle Total White Matter Sparing (mm 3 ) *** SCI-FluBZ SCI-Vehicle Total Gray Matter Sparing (mm 3 ) * SCI-FluBZ SCI-Vehicle FluBZ IP treatment, 3 hrs post-injury for 2 wks (1 mg/kg/day, n=1 per group)
15 J Clin Invest 29 Oct;119(1):299-9 B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice Ankeny DP, Guan Z, Popovich PG J Am Assoc Lab Anim Sci 29 May;48(3):251-7 Effects of fenbendazole on the murine humoral immune system Landin AM, Frasca D, Zaias J, Van der Put E, Riley RL, Altman NH, Blomberg BB FBZ suppresses B cell proliferation and production of antibodies Microtubule inhibitors (Colchicine, vinblastine): Cell cycle inhibition, antiinflammation, antiproliferation, and inhibition of perk1/2 (Gaba, 214, Spagnuolo, 21) 15
16 FBZ reduced IgG levels and CD45R-positive B cells at lesion site six weeks after SCI in mice Immunohistochemistry for IgG Immunofluorescence staining for CD45R-B cells CD45R DAPI Sham SCI-Control SCI+FBZ SCI-Control SCI-FBZ Sham Yu CG et al,
17 FLuBZ improves recovery of B cell population 4 weeks after SCI a Sham R3: 327% R3: 3539% b SCI+Vehicle c SCI+FluBZ R3: 2656% B-Cell Population (%) d # SCI+FluBZ 1mg/kg Sham SCI+Vehicle * 1 5 Flow cytometry analysis for CD45RA-positive B cell population 17
18 FluBZ inhibited ERK1/2, cyclin B1, and astroglial activation 4 wks after SCI ERK1/2 Activation Sham SCI+Vehicle SCI+FluBZ perk1 44 KDa perk2 42 KDa eif4e (25 KDa) (loading control) Cyclin B1 upregulation Cyclin B1 (58 kda) GAPDH (36 kda) Sham SCI+Vehicle SCI+FluBZ regulation APDH) Cyclin B1 Upr (Cyclin B1/GA Sham SCI+Vehicle SCI+FluBZ *** ## 1 Astroglial Activation A GFAP (43-45 kda) GAPDH (36 kda) Sham SCI+Vehicle SCI+FluBZ GFAP Expression (GFAP/GAPDH) B Sham SCI+Vehicle SCI+FluBZ *** ## 18
19 Brain Res Rev 29 Apr;6(1): doi: 1116/jbrainresrev Epub 28 Dec 25 MAP kinase and pain Ji RR 1, Gereau RW 4th, Malcangio M, Strichartz GR Life Sci 24 Apr 9;74(21): MAPK activation in nociceptive neurons and pain hypersensitivity Obata K 1, Noguchi K Rev Med Suisse 213 Jun 26;9(392): [Glial cells and chronic pain: from the laboratory to clinical hope] [Article in French] Clarke CB 1, Suter MR, Gosselin RD Eur J Pharmacol 213 Sep 15;716(1-3):12-8 doi: 1116/jejphar Epub 213 Mar 22 Astrocytes-- --multitaskers in chronic pain Hansen RR 1, Malcangio M 19
20 FluBZ attenuates pain behaviors after excitotoxic SCI in rats Grooming Onset Grooming Area Grooming Severity Grooming Onset (Days) QUIS+FluBZ 9 QUIS+FluBZ QUIS+Vehicle 8 QUIS+Vehicle Grooming Area (cm ) Grooming Severity QUIS+FluBZ QUIS+Vehicle Vehicle-treated FluBZ-treated Grooming incidence 75% 4% Onset grooming (days)
21 Summary for Part 2 (FBZ/FluBZ therapy) Fenbendazole and flubendazole Improve experimental outcomes following SCI Flubendazole inhibits perk1/2 cyclin B1 B-cell response astroglial activation Flubendazole is clinically approved and could easily be translated to human clinical trials 21
22 Future Direction SCI primary injury FluBZ G1 inhibit microtubule formation perk1/2 M S Molecular mechanisms Cyclin B1-CDK1 G2 cell cycle progression at G2/M B cells Astrocytes Microglia Cell nucleus Cellular mechanisms Autoimmune astroglial scar Inflammation, Nociception Pathological mechanisms Neuronal/axonal damage Failed axonal regeneration Locomotor deficits Chronic Pain Dysfunction 22
23 ACKNOWLEDGEMENTS Dr James W Geddes, PhD University of Kentucky Drs Yu/James W Geddes s lab Vimala Bondada Carolyn Crowdus Colin Rogers, PhD Kashif Raza Sarbani Ghoshal, PhD Ranjana Singh, PhD Brantley Graham Charles Mashburn, PhD Lauren Thompson Allie Zeller Lauren Power Mackenzie Jones Jessica Jones Dr Robert P Yezierski, PhD University of Florida Dr Hall s lab Dr Rabchevsky s lab Dr Saatman s lab Dr Springer s lab Dr Sullivan s lab Dr Snow s lab Dr Smith s lab Dr Bondada s lab Dr Gensel s lab Ms Zel Frye, Ms Liz Jones, Ms Julie Combs Dr Jeanie F Kincer Funding Sources University of Florida Seed Grant: Effects of ERK1/ERK2 sirna on Spinal Injury Pain PI: Chen Guang Yu, Paralysis Project of America Grant: Inhibition of ERK1/2 for treatment for spinal cord injury PI: Chen Guang Yu/James Geddes, KSCHIRT Grant 7-6A: Inhibition of ERK2 with lentiviral ERK2-shRNA for SCI PI: James Geddes/Chen Guang Yu, KSCHIRT Grant 11-19A: Calpain knockdown minimize damage and deficits after SCI PI: Chen Guang Yu/James Geddes, NIH CTSA Grant: ULTR117 PI: Chen Guang Yu,
CURRICULUM VITAE ~ Chen Guang Yu, M.D., Ph.D. CONTENT ORGANIZATION
CURRICULUM VITAE ~ Chen Guang Yu, M.D., Ph.D. I. GENERAL INFORMATION CONTENT ORGANIZATION II. III. IV. ACADEMIC APPOINTMENTS EDUCATION PROFESSIONAL EXPERIENCES V. HOSPITAL or CLINICAL APPOINTMENTS VI.
The Calpain / Calpastatin System in TBI and Chronic Neurodegeneration
The Calpain / Calpastatin System in TBI and Chronic Neurodegeneration Kathryn E. Saatman, Ph.D. Departments of Physiology and Neurosurgery Spinal Cord and Brain Injury Research Center Saatman lab: Dr.
Rapamycin suppresses astrocytic and microglial activation and reduces development of neuropathic pain after spinal cord injury in mice.
Rapamycin suppresses astrocytic and microglial activation and reduces development of neuropathic pain after spinal cord injury in mice. Satoshi Tateda, MD, Haruo Kanno, MD, PhD, Hiroshi Ozawa, MD, PhD,
SUPPLEMENTARY INFORMATION
Supplementary Figure 1. Behavioural effects of ketamine in non-stressed and stressed mice. Naive C57BL/6 adult male mice (n=10/group) were given a single dose of saline vehicle or ketamine (3.0 mg/kg,
Progress Report for NJCSCR (Yu-Wen Chang)
Progress Report for NJCSCR (Yu-Wen Chang) Overall Plan Summary: Traumatic injury to the spinal cord initiates a cascade of degenerative processes, known as secondary injury, which include various inflammatory
B-cell. Astrocyte SCI SCI. T-cell
RF #2015 P-01 PI: Azizul Haque, PhD Grant Title: Targeting Enolase in Spinal Cord Injury 12-month Technical Progress Report Progress Report (First Six Months): Enolase is one of the most abundantly expressed
CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5
The Journal of Clinical Investigation CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5 Bao-Chun Jiang, 1 De-Li Cao, 1 Xin Zhang, 1 Zhi-Jun Zhang, 1,2 Li-Na He, 1 Chun-Hua Li, 1
Supplemental Information. Menin Deficiency Leads to Depressive-like. Behaviors in Mice by Modulating. Astrocyte-Mediated Neuroinflammation
Neuron, Volume 100 Supplemental Information Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation Lige Leng, Kai Zhuang, Zeyue Liu, Changquan Huang,
SCIRF Award #2016 I-03 PI: Azizul Haque, PhD Grant Title: Neuron-specific Enolase and SCI
SCIRF Award #2016 I-03 PI: Azizul Haque, PhD Grant Title: Neuron-specific Enolase and SCI 10-month Technical Progress Report Enolase is a multifunctional glycolytic enzyme involved in growth control, hypoxia,
TBI: Translational Issues and Opportunities. Alan I Faden MD John Povlishock PhD
TBI: Translational Issues and Opportunities Alan I Faden MD John Povlishock PhD State of the Science: Translational Issues and Opportunities Translational Issues: Failed Clinical Trials - Animal Modeling
SUPPLEMENTARY FIG. S2. Representative counting fields used in quantification of the in vitro neural differentiation of pattern of dnscs.
Supplementary Data SUPPLEMENTARY FIG. S1. Representative counting fields used in quantification of the in vitro neural differentiation of pattern of anpcs. A panel of lineage-specific markers were used
Microglia, Inflammation, and FTD
FTD Minicourse April, 2009 Microglia, Inflammation, and FTD Li Gan, Ph.D Gladstone Institute of Neurological Disease University of California, San Francisco Outline Why study inflammation in neurodegeneration?
Research Development: Bedside to Bench and Back
Research Development: Bedside to Bench and Back Matt Bellizzi, MD PhD Department of Neurology University of Rochester School of Medicine and Dentistry Rochester, NY "I can walk down the hall just fine,
Diffuse brain injury causes up regulation of thrombospondins in the rat thalamus: Implications for a role in posttraumatic circuit reorganization
Diffuse brain injury causes up regulation of thrombospondins in the rat thalamus: Implications for a role in posttraumatic circuit reorganization Theresa Currier Thomas, PhD Lifshitz Lab Lexington, KY
Special Issue on Pain and Itch
Special Issue on Pain and Itch Title: Recent Progress in Understanding the Mechanisms of Pain and Itch Guest Editor of the Special Issue: Ru-Rong Ji, PhD Chronic pain is a major health problem world-wide.
Supplementary Figure 1
Supplementary Figure 1 AAV-GFP injection in the MEC of the mouse brain C57Bl/6 mice at 4 months of age were injected with AAV-GFP into the MEC and sacrificed at 7 days post injection (dpi). (a) Brains
Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development
Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development 1 Frankie Hang Fung Lee, 1 Ping Su, 1 Yu Feng Xie, 1 Kyle Ethan Wang, 2 Qi Wan and 1,3 Fang Liu 1 Campbell Research Institute, Centre
Supplementary Information
Supplementary Information Title Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis Authors Shin H. Kang, Ying Li, Masahiro Fukaya, Ileana Lorenzini,
Modulation of TRP channels by resolvins in mouse and human
July 9, 2015, Ion Channel Retreat, Vancouver Ion Channel and Pain Targets Modulation of TRP channels by resolvins in mouse and human Ru-Rong Ji, PhD Pain Research Division Department of Anesthesiology
Supplementary Materials for
www.sciencesignaling.org/cgi/content/full/6/283/ra57/dc1 Supplementary Materials for JNK3 Couples the Neuronal Stress Response to Inhibition of Secretory Trafficking Guang Yang,* Xun Zhou, Jingyan Zhu,
Effect of rolipram-loaded polymeric micelle nanoparticle on camp level in hypoxia condition and in rat SCI model
Effect of rolipram-loaded polymeric micelle nanoparticle on camp level in hypoxia condition and in rat SCI model 1 Christian Macks, 1 So Jung Gwak, PhD, 2 Michael Lynn, MD, 1 JeoungSoo Lee, PhD. 1 Bioengineering,
In vivo reprogramming reactive glia into ipscs to produce new neurons in the
In vivo reprogramming reactive glia into ipscs to produce new neurons in the cortex following traumatic brain injury Xiang Gao 1, Xiaoting Wang 1, Wenhui Xiong 1, Jinhui Chen 1, * 1 Spinal Cord and Brain
Is Spinal Cord Repair a Reality? Schwann Cell Transplantation for Subacute Spinal Cord Injury
Is Spinal Cord Repair a Reality? Schwann Cell Transplantation for Subacute Spinal Cord Injury James Guest MD, PhD, FACS Clinical Professor of Neurological Surgery, Neurosurgery and the Miami Project to
Treatments for Acute Spinal Cord Injury. Jim Geddes Spinal Cord and Brain Injury Research Center University of Kentucky
Treatments for Acute Spinal Cord Injury Jim Geddes Spinal Cord and Brain Injury Research Center University of Kentucky FDA Approved Drugs for Acute SCI Progress to date 5017 140 NIH funding ~$142 million/yr
NNZ-2566 in Rett Syndrome and Autism Spectrum Disorders Role and Update
NNZ-2566 in Rett Syndrome and Autism Spectrum Disorders Role and Update 1 Overview The natural growth factor IGF-1 is broken down in the body to IGF-1[1-3] NNZ-2566 is an analogue of IGF-1[1-3] developed
GFP/Iba1/GFAP. Brain. Liver. Kidney. Lung. Hoechst/Iba1/TLR9!
Supplementary information a +KA Relative expression d! Tlr9 5!! 5! NSC Neuron Astrocyte Microglia! 5! Tlr7!!!! NSC Neuron Astrocyte! GFP/Sβ/! Iba/Hoechst Microglia e Hoechst/Iba/TLR9! GFP/Iba/GFAP f Brain
Jacqueline Renee Kulbe
Jacqueline Renee Kulbe Doctoral Candidate Department of Neuroscience Spinal Cord & Brain Injury Research Center MD-PhD Program, University of Kentucky College of Medicine Jacqueline.Kulbe@uky.edu Education
Supplemental Figures:
Supplemental Figures: Figure 1: Intracellular distribution of VWF by electron microscopy in human endothelial cells. a) Immunogold labeling of LC3 demonstrating an LC3-positive autophagosome (white arrow)
Supplementary Figure 1
Supplementary Figure 1 3 3 3 1 1 Bregma -1.6mm 3 : Bregma Ref) Http://www.mbl.org/atlas165/atlas165_start.html Bregma -.18mm Supplementary Figure 1 Schematic representation of the utilized brain slice
Neuroprotection in preclinical models of Parkinson disease by the NAPVSIPQ peptide
Neuroprotection in preclinical models of Parkinson disease by the NAPVSIPQ peptide Bruce H. Morimoto, Ph.D. Executive Director, Applied Translational Medicine Microtubules Microtubules essential for neuronal
effect on the upregulation of these cell surface markers. The mean peak fluorescence intensity
SUPPLEMENTARY FIGURE 1 Supplementary Figure 1 ASIC1 disruption or blockade does not effect in vitro and in vivo antigen-presenting cell activation. (a) Flow cytometric analysis of cell surface molecules
Primary oligodendropathy is not a trigger of CNS autoimmunity
Primary oligodendropathy is not a trigger of CNS autoimmunity Ari Waisman Institute for Molecular Medicine University Medical Center, JGU Mainz 1 How is an anti-myelin immune response initiated? Secondary
Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan, 2
Low-energy Extracorporeal Shock Wave Therapy Promotes VEGF Expression and Angiogenesis and Improve Locomotor and Sensory Functions after spinal cord injury Kenichiro Yahata 1, Hiroshi Ozawa, M.D., Ph.D.
Astragaloside IV ameliorates 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced
Astragaloside IV ameliorates 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis implicating regulation of energy metabolism Xu-Guang Jiang 1,2,, Kai Sun 1,3,4,5,, Yu-Ying Liu 1,4,5, Li Yan 1,4,5,
c Ischemia (30 min) Reperfusion (8 w) Supplementary Figure bp 300 bp Ischemia (30 min) Reperfusion (4 h) Dox 20 mg/kg i.p.
a Marker Ripk3 +/ 5 bp 3 bp b Ischemia (3 min) Reperfusion (4 h) d 2 mg/kg i.p. 1 w 5 w Sacrifice for IF size A subset for echocardiography and morphological analysis c Ischemia (3 min) Reperfusion (8
Supplementary Figure 1: si-craf but not si-braf sensitizes tumor cells to radiation.
Supplementary Figure 1: si-craf but not si-braf sensitizes tumor cells to radiation. (a) Embryonic fibroblasts isolated from wildtype (WT), BRAF -/-, or CRAF -/- mice were irradiated (6 Gy) and DNA damage
SUPPLEMENTARY INFORMATION. Supplementary Figures S1-S9. Supplementary Methods
SUPPLEMENTARY INFORMATION SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane Jian Huang 1,2#, Jie Yan 1,2#, Jian Zhang 3#, Shiguo Zhu 1, Yanli Wang
3rd International Conference on Neurology & Therapeutics.
3rd International Conference on Neurology & Therapeutics www.neuroimmunology.ca Multiple sclerosis is a devastating disease The first description of the disease was mentioned in 14th century In 1838 Dr.
Neuroplasticity. Drs. Bieberich, Frolenkov, Gensel, Lee, McClintock, Rabchevsky, Saatman, Smith, Taylor, Wilson
Neuroplasticity Drs. Bieberich, Frolenkov, Gensel, Lee, McClintock, Rabchevsky, Saatman, Smith, Taylor, Wilson Ceramide is a membrane sphingolipid at the interface of basic and translational neuroscience.
Supplementary Figure 1. Microglia do not show signs of classical immune activation following MD a-b. Images showing immunoreactivity for MHCII (a)
1 Supplementary Figure 1. Microglia do not show signs of classical immune activation following MD a-b. Images showing immunoreactivity for MHCII (a) and CD45 (b) in fixed sections of binocular visual cortex
Supplemental Materials for. Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to. FTY720 during neuroinflammation
Supplemental Materials for Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY7 during neuroinflammation This file includes: Supplemental Table 1. EAE clinical parameters of
What Cell Make Up the Brain and Spinal Cord
What Cell Make Up the Brain and Spinal Cord Jennifer LaVail, Ph.D. (http://anatomy.ucsf.edu/pages/lavaillab/index.html) What kinds of cells are these?" Neuron?" Epithelial cell?" Glial cell?" What makes
Cannabinoid Agonists Inhibit Neuropathic Pain Induced by Brachial Plexus Avulsion in Mice by Affecting Glial Cells and MAP Kinases
Cannabinoid Agonists Inhibit Neuropathic Pain Induced by Brachial Plexus Avulsion in Mice by Affecting Glial Cells and MAP Kinases Ana F. Paszcuk 1, Rafael C. Dutra 1, Kathryn A. B. S. da Silva 1, Nara
Lack of GPR88 enhances medium spiny neuron activity and alters. motor- and cue- dependent behaviors
Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue- dependent behaviors Albert Quintana, Elisenda Sanz, Wengang Wang, Granville P. Storey, Ali D. Güler Matthew J. Wanat, Bryan
Supplementary Figure 1. Spatial distribution of LRP5 and β-catenin in intact cardiomyocytes. (a) and (b) Immunofluorescence staining of endogenous
Supplementary Figure 1. Spatial distribution of LRP5 and β-catenin in intact cardiomyocytes. (a) and (b) Immunofluorescence staining of endogenous LRP5 in intact adult mouse ventricular myocytes (AMVMs)
Supplementary Figure 1. Repression of hepcidin expression in the liver of mice treated with
Supplementary Figure 1. Repression of hepcidin expression in the liver of mice treated with DMN Immunohistochemistry for hepcidin and H&E staining (left). qrt-pcr assays for hepcidin in the liver (right).
Rapamycin Suppresses Astrocytic and Microglial Activation and Reduced Development of Neuropathic Pain after Spinal Cord Injury in Mice.
Rapamycin Suppresses Astrocytic and Microglial Activation and Reduced Development of Neuropathic Pain after Spinal Cord Injury in Mice. Satoshi Tateda, M.D., Haruo Kanno, M.D., Ph.D., Hiroshi Ozawa, M.D.,
Supplementary Figure 1. Validation of astrocytes. Primary astrocytes were
Supplementary Figure 1. Validation of astrocytes. Primary astrocytes were separated from the glial cultures using a mild trypsinization protocol. Anti-glial fibrillary acidic protein (GFAP) immunofluorescent
Role of the Chondroitin Sulfate Proteoglycan, Neurocan, in Inhibition of Sensory Neurite Regeneration
University of Kentucky UKnowledge Lewis Honors College Capstone Collection Lewis Honors College 2016 Role of the Chondroitin Sulfate Proteoglycan, Neurocan, in Inhibition of Sensory Neurite Regeneration
Title of file for HTML: Supplementary Information Description: Supplementary Figures and Supplementary Table
Title of file for HTML: Supplementary Information Description: Supplementary Figures and Supplementary Table Title of file for HTML: Peer Review File Description: Innate Scavenger Receptor-A regulates
Review and Public RAC Discussion of Protocol #
Review and Public RAC Discussion of Protocol #0508 725 A phase I pilot study of safety and feasibility of stem cell therapy for AIDS lymphoma using stem cells treated with a lentivirus vector encoding
I. Paterniti, M. Campolo, M. Cordaro, D. Impellizzeri, R. Siracusa, R. Crupi, E. Esposito, and S. Cuzzocrea. University of Messina, Italy
I. Paterniti, M. Campolo, M. Cordaro, D. Impellizzeri, R. Siracusa, R. Crupi, E. Esposito, and S. Cuzzocrea University of Messina, Italy A spinal cord lesion is a partial or total disruption of the structural
Hole s Human Anatomy and Physiology Tenth Edition. Chapter 10
PowerPoint Lecture Outlines to accompany Hole s Human Anatomy and Physiology Tenth Edition Shier Butler Lewis Chapter 10 Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or
Supplementary Materials
Supplementary Materials Fig. S1. Weights of full-dose treatment groups comparing 1 st, 2 nd, and 3 rd generation gene replacement therapy. Mice were treated at p1 with 4x10 11 GC of the three different
SUPPLEMENTARY INFORMATION
doi: 10.1038/nature06994 A phosphatase cascade by which rewarding stimuli control nucleosomal response A. Stipanovich*, E. Valjent*, M. Matamales*, A. Nishi, J.H. Ahn, M. Maroteaux, J. Bertran-Gonzalez,
Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture
Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture Nanna Goldman *, Michael Chen *, Takumi Fujita *, Qiwu Xu, Weiguo Peng, Wei Liu, Tina K. Jensen, Yong Pei, Fushun Wang, Xiaoning
Amniotic fluid stem cells provide considerable advantages in epidermal. regeneration: B7H4 creates a moderate inflammation
Amniotic fluid stem cells provide considerable advantages in epidermal regeneration: B7H4 creates a moderate inflammation microenvironment to promote wound repair Qing Sun 1, +, Fang Li 1, +, Hong Li 2,
Supplemental Figure 1. Western blot analysis indicated that MIF was detected in the fractions of
Supplemental Figure Legends Supplemental Figure 1. Western blot analysis indicated that was detected in the fractions of plasma membrane and cytosol but not in nuclear fraction isolated from Pkd1 null
CHAPTER 2 LITERATURE REVIEW. Glaucoma is a devastating, worldwide disease. In just the United States there are over 2
CHAPTER 2 LITERATURE REVIEW Introduction Glaucoma is a devastating, worldwide disease. In just the United States there are over 2 million estimated cases with 120,000 of those responsible for blindness.
Supplementary Figure 1. Confocal immunofluorescence showing mitochondrial translocation of Drp1. Cardiomyocytes treated with H 2 O 2 were prestained
Supplementary Figure 1. Confocal immunofluorescence showing mitochondrial translocation of Drp1. Cardiomyocytes treated with H 2 O 2 were prestained with MitoTracker (red), then were immunostained with
Nature Neuroscience: doi: /nn Supplementary Figure 1. Splenic atrophy and leucopenia caused by T3 SCI.
Supplementary Figure 1 Splenic atrophy and leucopenia caused by T3 SCI. (a) Gross anatomy of representative spleens from control and T3 SCI mice at 28 days post-injury. (b and c) Hematoxylin and eosin
Supplemental Materials
Supplemental Materials Programmed death one homolog maintains the pool size of regulatory T cells by promoting their differentiation and stability Qi Wang 1, Jianwei He 1, Dallas B. Flies 2, Liqun Luo
February 14, 2003 Report on preclinical studies in gc-ko mice Fabio Candotti
February 14, 2003 Report on preclinical studies in gc-ko mice Fabio Candotti Five published reports (see details below) have described the development of peripheral blood lymphocytes as well as cellular
IVIg attenuates complement and improves spinal cord injury outcomes in mice
RESEARCH ARTICLE IVIg attenuates complement and improves spinal cord injury outcomes in mice Faith H. Brennan 1, Nyoman D. Kurniawan 2, Jana Vukovic 1,3, Perry F. Bartlett 3, Fabian K asermann 4, Thiruma
Cells and reagents. Synaptopodin knockdown (1) and dynamin knockdown (2)
Supplemental Methods Cells and reagents. Synaptopodin knockdown (1) and dynamin knockdown (2) podocytes were cultured as described previously. Staurosporine, angiotensin II and actinomycin D were all obtained
Receptor-interacting Protein Kinases Mediate Necroptosis In Neural Tissue Damage After Spinal Cord Injury
Receptor-interacting Protein Kinases Mediate Necroptosis In Neural Tissue Damage After Spinal Cord Injury Haruo Kanno, M.D., Ph.D., Hiroshi Ozawa, M.D., Ph.D., Satoshi Tateda, M.D., Kenichiro Yahata, M.D.,
Supplementary Information Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice
Supplementary Information Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice Wang et. al. IL-6 in plasma (pg/ml) Rac1/HPRT (% of control) PSD9/HPRT
M2 microglia/ macrophages drive oligodendrocyte differentiation during CNS remyelination
Supplemental Information Title: M2 microglia/ macrophages drive oligodendrocyte differentiation during CNS remyelination Authors: Veronique E. Miron, Amanda Boyd, Jing-Wei Zhao, Tracy J. Yuen, Julia M.
Supplemental Information
Supplemental Information Tobacco-specific Carcinogen Induces DNA Methyltransferases 1 Accumulation through AKT/GSK3β/βTrCP/hnRNP-U in Mice and Lung Cancer patients Ruo-Kai Lin, 1 Yi-Shuan Hsieh, 2 Pinpin
SUPPLEMENTARY FIGURE LEGENDS. atypical adenomatous hyperplasias (AAH); Grade II: adenomas; Grade III: adenocarcinomas;
SUPPLEMENTARY FIGURE LEGENDS Supplementary Figure S1: Tumor grades in Ras G12D ; p53 / lung tumors. Representative histology (H&E) of K-Ras G12D ; p53 / lung tumors 13 weeks after tumor initiation. Grade
and follicular helper T cells is Egr2-dependent. (a) Diagrammatic representation of the
Supplementary Figure 1. LAG3 + Treg-mediated regulation of germinal center B cells and follicular helper T cells is Egr2-dependent. (a) Diagrammatic representation of the experimental protocol for the
BioMed Central. Jeannette E Davies*, Christoph Pröschel, Ningzhe Zhang, Mark Noble, Margot Mayer-Pröschel and Stephen JA Davies* Research article
BioMed Central Open Access Research article Transplanted astrocytes derived from BMP- or CNTF-treated glialrestricted precursors have opposite effects on recovery and allodynia after spinal cord injury
SUPPLEMENTARY FIGURES
SUPPLEMENTARY FIGURES 1 Supplementary Figure 1, Adult hippocampal QNPs and TAPs uniformly express REST a-b) Confocal images of adult hippocampal mouse sections showing GFAP (green), Sox2 (red), and REST
Supplementary Figures
Supplementary Figures Supplementary Figure 1. NKT ligand-loaded tumour antigen-presenting B cell- and monocyte-based vaccine induces NKT, NK and CD8 T cell responses. (A) The cytokine profiles of liver
TITLE: Harnessing GPR17 Biology for Treating Demyelinating Disease
AD Award Number: W81XWH-10-1-0721 TITLE: Harnessing GPR17 Biology for Treating Demyelinating Disease PRINCIPAL INVESTIGATOR: Nitin Karandikar, M.D., Ph.D. CONTRACTING ORGANIZATION: University of Texas
Nature Neuroscience: doi: /nn.4335
Supplementary Figure 1 Cholinergic neurons projecting to the VTA are concentrated in the caudal mesopontine region. (a) Schematic showing the sites of retrograde tracer injections in the VTA: cholera toxin
Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion
Wu et al. Journal of Neuroinflammation 2012, 9:169 JOURNAL OF NEUROINFLAMMATION RESEARCH Open Access Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation
The Opportunity: Parkinson s disease, RLS, ADHD, and disease modification YKP10461
The Opportunity: Parkinson s disease, RLS, ADHD, and disease modification YKP10461 1 TABLE OF CONTENTS Profile Summary Mechanism of Action Clinical Study Results Pharmacologic Profile Safety and Toxicity
Supporting Information. Calculation of the relative contributions of myocyte proliferation, stem cell. Supporting Information Fig 1 (page 9)
Supporting Information Table of contents Calculation of the relative contributions of myocyte proliferation, stem cell differentiation and cardioprotection (page 2) Supporting Information Fig 1 (page 9)
Multiple Sclerosis and Neuroinflammation: Considering Gender differences to design therapeutic agents HALINA OFFNER
Multiple Sclerosis and Neuroinflammation: Considering Gender differences to design therapeutic agents HALINA OFFNER Sex differences in autoimmune disease Ratio Target Sex distribution of major autoimmune
Liz et al. BMC Biology 2014, 12:47
Liz et al. BMC Biology 2014, 12:47 RESEARCH ARTICLE Neuronal deletion of GSK3β increases microtubule speed in the growth cone and enhances axon regeneration via CRMP-2 and independently of MAP1B and CLASP2
Supplementary. presence of the. (c) mrna expression. Error. in naive or
Figure 1. (a) Naive CD4 + T cells were activated in the presence of the indicated cytokines for 3 days. Enpp2 mrna expression was measured by qrt-pcrhr, infected with (b, c) Naive CD4 + T cells were activated
Anatomy of a Neuron. Copyright 2000 by BSCS and Videodiscovery, Inc. Permission granted for classroom use. Updated Master 2.
Anatomy of a Neuron Master 2.1 Neurons Interact with Other Neurons through Synapses Master 2.2 Name Date Due Cells of the Nervous System Learning Target: Identify and state the function of the components
Cord blood monocytes as a source of cell therapy products for treatment of brain injuries ISCT/CBA 2015 Cord Blood Workshop Wednesday, May 27, 2015
Cord blood monocytes as a source of cell therapy products for treatment of brain injuries ISCT/CBA 2015 Cord Blood Workshop Wednesday, May 27, 2015 Andrew E. Balber, PhD Senior Scientific Advisor CT 2,
RCPA Research Award Final Progress Review
RCPA Research Award 2010-2011 Final Progress Review Name: Dr Craig Wallington-Beddoe Degree/Institution/Year: PhD, The University of Sydney, Year 2 Research Project Title: New Therapeutic Strategies for
Supplementary Figure 1. Deletion of Smad3 prevents B16F10 melanoma invasion and metastasis in a mouse s.c. tumor model.
A B16F1 s.c. Lung LN Distant lymph nodes Colon B B16F1 s.c. Supplementary Figure 1. Deletion of Smad3 prevents B16F1 melanoma invasion and metastasis in a mouse s.c. tumor model. Highly invasive growth
Supplementary Fig. 1. GPRC5A post-transcriptionally down-regulates EGFR expression. (a) Plot of the changes in steady state mrna levels versus
Supplementary Fig. 1. GPRC5A post-transcriptionally down-regulates EGFR expression. (a) Plot of the changes in steady state mrna levels versus changes in corresponding proteins between wild type and Gprc5a-/-
Supplemental Figure 1. Intracranial transduction of a modified ptomo lentiviral vector in the mouse
Supplemental figure legends Supplemental Figure 1. Intracranial transduction of a modified ptomo lentiviral vector in the mouse hippocampus targets GFAP-positive but not NeuN-positive cells. (A) Stereotaxic
Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice
Zhang et al. Journal of Neuroinflammation (2016) 13:183 DOI 10.1186/s12974-016-0652-1 RESEARCH Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice
AP VP DLP H&E. p-akt DLP
A B AP VP DLP H&E AP AP VP DLP p-akt wild-type prostate PTEN-null prostate Supplementary Fig. 1. Targeted deletion of PTEN in prostate epithelium resulted in HG-PIN in all three lobes. (A) The anatomy
Supplementary Figure 1. IHC and proliferation analysis of pten-deficient mammary tumors
Wang et al LEGENDS TO SUPPLEMENTARY INFORMATION Supplementary Figure 1. IHC and proliferation analysis of pten-deficient mammary tumors A. Induced expression of estrogen receptor α (ERα) in AME vs PDA
SUPPLEMENTARY INFORMATION
DOI: 10.1038/ncb3461 In the format provided by the authors and unedited. Supplementary Figure 1 (associated to Figure 1). Cpeb4 gene-targeted mice develop liver steatosis. a, Immunoblot displaying CPEB4
Risk Factors That Predispose Patients to Orofacial Pain
Risk Factors That Predispose Patients to Orofacial Pain Paul Durham, PhD Distinguished Professor of Cell Biology Director Center for Biomedical & Life Sciences Missouri State University Cluster Headache
1,8 1,6 1,4 1,2 1. EE/g lean mass 0,8 0,6 0,4 0,2. Ambulatory locomotor activity. (beam brakes/48h) V MCH MCHpf 0,86 0,85 0,84 0,83 0,82 0,81 0,8
Supplementary figure 1 vehicle A -pf Energy expenditure (kcal/kg/48h) 25 2 15 1 5 V pf EE/g lean mass 1,8 1,6 1,4 1,2 1,8,6,4,2 Total locomotor activity (beam brakes/48h) C D E 7 6 5 4 3 2 1 V pf Ambulatory
Myelin suppresses axon regeneration by PIR-B/SHPmediated inhibition of Trk activity
Manuscript EMBO-2010-76298 Myelin suppresses axon regeneration by PIR-B/SHPmediated inhibition of Trk activity Yuki Fujita, Shota Endo, Toshiyuki Takai and Toshihide Yamashita Corresponding author: Toshihide
Peli1 negatively regulates T-cell activation and prevents autoimmunity
Peli1 negatively regulates T-cell activation and prevents autoimmunity Mikyoung Chang 1,*, Wei Jin 1,5,*, Jae-Hoon Chang 1, Yi-chuan Xiao 1, George Brittain 1, Jiayi Yu 1, Xiaofei Zhou 1, Yi-Hong Wang
Supplementary Figure 1. Baf60c and baf180 are induced during cardiac regeneration in zebrafish. RNA in situ hybridization was performed on paraffin
Supplementary Figure 1. Baf60c and baf180 are induced during cardiac regeneration in zebrafish. RNA in situ hybridization was performed on paraffin sections from sham-operated adult hearts (a and i) and
Bitter Taste Receptors: Taking a Bigger Bite of Airway Smooth Muscle Pathophysiology
Page 1 of 6 Editorial Bitter Taste Receptors: Taking a Bigger Bite of Airway Smooth Muscle Pathophysiology Charles W. Emala, Sr. Department of Anesthesiology Columbia University, New York, New York Contact
Supplementary Figure 1. Blood glucose and insulin levels in mice during 4-day infusion.
Supplementary Figure 1. Blood glucose and insulin levels in mice during 4-day infusion. (A-B) WT and HT mice infused with saline or glucose had overlapping achieved blood glucose and insulin levels, necessitating
Selective filtering defect at the axon initial segment in Alzheimer s disease mouse models. Yu Wu
Selective filtering defect at the axon initial segment in Alzheimer s disease mouse models Yu Wu Alzheimer s Disease (AD) Mouse models: APP/PS1, PS1δE9, APPswe, hps1 Wirths, O. et al, Acta neuropathologica