Department of Dermatology Works

Permanent URI for this collection

https://hdl.handle.net/1805/7623

Browse

Browsing Department of Dermatology Works by Issue Date

Filter results by year or month
Now showing 1 - 10 of 172
  • Thumbnail Image
    Item
    Differential regulation of the SMN2 gene by individual HDAC proteins
    (Elsevier, 2011-10-14) Evans, Matthew C.; Cherry, Jonathan J.; Androphy, Elliot J.; Dermatology, School of Medicine
    Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that is the leading genetic cause of infantile death. SMA is caused by homozygous deletion or mutation of the survival of motor neuron 1 gene (SMN1). The SMN2 gene is nearly identical to SMN1, however is alternatively spliced. The close relationship to SMN1 results in SMN2 being a very power genetic modifier of SMA disease severity and a target for therapies. We sought to identify the regulatory role individual HDAC proteins use to control expression of full length protein from the SMN2 genes. We used quantitative PCR to determine the effects shRNA silencing of individual HDACs on the steady state levels of a SMN2-luciferase reporter transcripts. We determined that reduction of individual HDAC proteins was sufficient to increase SMN protein levels in a transgenic reporter system. Knockdown of class I HDAC proteins preferentially activated the reporter by increased promoter transcription. Silencing of class II HDAC proteins maintained transcriptional activity; however silencing of HDAC 5 and 6 also appeared to enhance inclusion of an alternatively spliced exon. This work highlights HDAC proteins 2 and 6 as excellent investigative targets. These data are important to the basic understanding of SMN expression regulation and the refinements of current therapeutic compounds as well as the development of novel SMA therapeutics.
  • Thumbnail Image
    Item
    Dilysine motifs in exon 2b of SMN protein mediate binding to the COPI vesicle protein α-COP and neurite outgrowth in a cell culture model of spinal muscular atrophy
    (Oxford Journals, 2013-10-15) Custer, Sara K.; Todd, Adrian G.; Singh, Natalia N.; Androphy, Elliot J.; Department of Dermatology, School of Medicine
    Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder that stems from low levels of survival of motor neuron (SMN) protein. The processes that cause motor neurons and muscle cells to become dysfunctional are incompletely understood. We are interested in neuromuscular homeostasis and the stresses put upon that system by loss of SMN. We recently reported that α-COP, a member of the coatomer complex of coat protein I (COPI) vesicles, is an SMN-binding partner, implicating this protein complex in normal SMN function. To investigate the functional significance of the interaction between α-COP and SMN, we constructed an inducible NSC-34 cell culture system to model the consequences of SMN depletion and find that depletion of SMN protein results in shortened neurites. Heterologous expression of human SMN, and interestingly over-expression of α-COP, restores normal neurite length and morphology. Mutagenesis of the canonical COPI dilysine motifs in exon 2b results in failure to bind to α-COP and abrogates the ability of human SMN to restore neurite outgrowth in SMN-depleted motor neuron-like NSC-34 cells. We conclude that the interaction between SMN and α-COP serves an important function in the growth and maintenance of motor neuron processes and may play a significant role in the pathogenesis of SMA.
  • Thumbnail Image
    Item
    Autophagy dysregulation in cell culture and animals models of Spinal Muscular Atrophy
    (Elsevier, 2014-07) Custer, Sara K.; Androphy, Elliot J.; Department of Dermatology, IU School of Medicine
    Abnormal autophagy has become a central thread linking neurodegenerative diseases, particularly of the motor neuron. One such disease is spinal muscular atrophy (SMA), a genetic neuromuscular disorder caused by mutations in the SMN1 gene resulting in low levels of Survival Motor Neuron (SMN) protein. Despite knowing the causal protein, the exact intracellular processes that are involved in the selective loss of motor neurons remains unclear. Autophagy induction can be helpful or harmful depending on the situation, and we sought to understand the state of the autophagic response in SMA. We show that cell culture and animal models demonstrate induction of autophagy accompanied by attenuated autophagic flux, resulting in the accumulation of autophagosomes and their associated cargo. Expression of the SMN-binding protein a-COP, a known modulator of autophagic flux, can ameliorate this autophagic traffic jam.
  • Thumbnail Image
    Item
    Toxic interaction between Th2 cytokines and Staphylococcus aureus in atopic dermatitis
    (Nature Publishing Group, 2014-08) Travers, Jeffrey B.; Department of Dermatology, IU School of Medicine
    Patients with atopic dermatitis (AD) are commonly colonized/infected with Staphylococcus aureus, and this bacterium is known to worsen the dermatitis. In this issue, Brauweiler et al. demonstrate a newly discovered mechanism by which Th2 cytokines involved in AD augments the toxicity of the lytic staphylococcal protein alpha toxin. This review presents mechanisms by which Th2 cytokines may interact with S. aureus to the detriment of the dermatitis.
  • Thumbnail Image
    Item
    Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor
    (American Association for Cancer Research, 2014-12-01) Sahu, Ravi P.; Ocana, Jesus A.; Harrison, Kathleen A.; Ferracini, Matheus; Touloukian, Christopher E.; Al-Hassani, Mohammed; Sun, Louis; Loesch, Mathew; Murphy, Robert C.; Althouse, Sandra K.; Perkins, Susan M.; Speicher, Paul J.; Tyler, Douglas S.; Konger, Raymond L.; Travers, Jeffrey B.; Department of Dermatology, IU School of Medicine
    Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation.
  • Thumbnail Image
    Item
    Ferroxitosis: a cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma
    (Impact Journals, LLC, 2014-12-30) Lakhter, Alexander J.; Hamilton, James; Dagher, Pierre C.; Mukkamala, Suresh; Hato, Takashi; Dong, X. Charlie; Mayo, Lindsey D.; Harris, Robert A.; Shekhar, Anantha; Ivan, Mircea; Brustovetsky, Nickolay; Naidu, Samisubbu R.; Department of Dermatology, IU School of Medicine
    Reliance on glycolysis is a characteristic of malignancy, yet the development of resistance to BRAF inhibitors in melanoma is associated with gain of mitochondrial function. Concurrent attenuation of oxidative phosphorylation and HIF-1α/PKM2-dependent glycolysis promotes a non-apoptotic, iron- and oxygen-dependent cell death that we term ferroxitosis. The redox cycling agent menadione causes a robust increase in oxygen consumption, accompanied by significant loss of intracellular ATP and rapid cell death. Conversely, either hypoxic adaptation or iron chelation prevents menadione-induced ferroxitosis. Ectopic expression of K213Q HIF-1α mutant blunts the effects of menadione. However, knockdown of HIF-1α or PKM2 restores menadione-induced cytotoxicity in hypoxia. Similarly, exposure of melanoma cells to shikonin, a menadione analog and a potential PKM2 inhibitor, is sufficient to induce ferroxitosis under hypoxic conditions. Collectively, our findings reveal that ferroxitosis curtails metabolic plasticity in melanoma.
  • Thumbnail Image
    Item
    Discrete and Coalescing Pustules Masking Severe Recalcitrant Rosacea due to Demodex
    (OMICS International, 2015) Stefanie Ali, Chase Wilson; Megan Brinkworth, Nico Mousdicas; Dermatology, School of Medicine
    We describe a clinical case concerning a 36 year old man with a recalcitrant dermatosis involving the face and neck to demonstrate how multiple pathogenic mechanisms may ultimately prohibit disease resolution. This patient’s disease persisted despite multiple standard treatments for the leading differential diagnoses early in the disease course including: topical/systemic corticosteroids for an initially suspected facial dermatitis followed by minocycline and oral ivermectin for granulomatous rosacea with high Demodex burden. These failed therapies prompted the use of oral prednisone and topical pimecrolimus that resulted in some improvement but worsening flares if therapy was discontinued. The leading differential shifted toward rosacea fulminans or an unusual manifestation of immune reconstitution inflammatory syndrome (IRIS) in the setting of possible HIV or iatrogenic immunosuppression. An extensive diagnostic workup was completed and showed isolated IgM deficiency (49 mg/dl, normal range 60 to 300 mg/dl), low levels of 25 hydroxyvitamin D (15 pg/mL, normal range 18 to 64 pg/mL), and low ascorbic acid (0.3 mg/dl, normal range 0.6 to 2.0 mg/dl). The rash finally resolved following a tapering course of cyclosporine and vitamin repletion through supplements and dietary alteration. Our case is one with multiple confounding variables that may have contributed to the recalcitrant nature of this dermatosis: (1) presence of Demodex; (2) iatrogenic immunosuppression due to prolonged systemic and topical steroid use; and (3) vitamin deficiency. It is unclear exactly what role each of these factors played but the purpose of our case is to illustrate these variables can be encountered in regular practice and that sometimes the physician must explore and correct all potential vectors of pathogenesis in order to successfully treat recalcitrant dermatoses.
  • Thumbnail Image
    Item
    Topical photodynamic therapy induces systemic immunosuppression via generation of platelet-activating factor receptor ligands
    (Nature Publishing Group, 2015-01) Ferracini, Matheus; Sahu, Ravi P.; Harrison, Kathleen A.; Waeiss, Robert A.; Murphy, Robert C.; Jancar, Sonia; Konger, Raymond L.; Travers, Jeffrey B.; Department of Dermatology, IU School of Medicine
  • Thumbnail Image
    Item
    Levels of the E2 interacting protein TopBP1 modulate papillomavirus maintenance stage replication
    (Elsevier, 2015-04) Kanginakudru, Sriramana; DeSmet, Marsha; Thomas, Yanique; Morgan, Iain M.; Androphy, Elliot J.; Department of Dermatology, IU School of Medicine
    The evolutionarily conserved DNA topoisomerase II beta-binding protein 1 (TopBP1) functions in DNA replication, DNA damage response, and cell survival. We analyzed the role of TopBP1 in human and bovine papillomavirus genome replication. Consistent with prior reports, TopBP1 co-localized in discrete nuclear foci and was in complex with papillomavirus E2 protein. Similar to E2, TopBP1 is recruited to the region of the viral origin of replication during G1/S and early S phase. TopBP1 knockdown increased, while over-expression decreased transient virus replication, without affecting cell cycle. Similarly, using cell lines harboring HPV-16 or HPV-31 genome, TopBP1 knockdown increased while over-expression reduced viral copy number relative to genomic DNA. We propose a model in which TopBP1 serves dual roles in viral replication: it is essential for initiation of replication yet it restricts viral copy number.
  • Thumbnail Image
    Item
    The Reverse Galeal Hinge Flap: Another Valuable Technique in the Repair of Scalp Defects Extending to the Calvarium
    (Lippincott Williams & Wilkins, 2015-04) Lam, Thomas; Miletta, Nathanial R.; Bingham, Jonathan L.; Department of Dermatology, IU School of Medicine
    Over the last 30 years, the estimated incidence of nonmelanoma skin cancer (NMSC) has increased from 300,000 to greater than 2 million cases. Approximately 15% of these cancers occur on the scalp.1 Given the increasing incidence of NMSC and their predilection for the scalp, the demand for scalp repairs will continue to rise. It is important that the dermatologic surgeon is equipped to manage these cases, in particular defects that extend to the bone.The repair of large scalp defects extending to the calvarium is especially challenging for several reasons. The primary closure of any large scalp wound is complicated by the relative inelasticity of scalp tissue and the convexity of the scalp. Rotation flaps are the mainstay technique of re-approximating large scalp wounds but are often unable to completely close very large defects.2 Skin grafts can also be used to cover wounds primarily or in conjunction with other closure techniques.2 However, when scalp defects extend to the bone, the poor vascularity of the osseous tissue severely limits both skin grafting and xenografting. Various approaches to making exposed bone more suitable for grafting have been described in the recent literature, and these techniques and their limitations will be briefly discussed.3–5 The authors will also present two cases that outline a simple method of re-establishing a vascular bed on exposed bone using a reverse galeal hinge flap.