Department of Ophthalmology Works

Permanent URI for this collection

https://hdl.handle.net/1805/4123

Browse

Browsing Department of Ophthalmology Works by Issue Date

Filter results by year or month
Now showing 1 - 10 of 346
  • Thumbnail Image
    Item
    Molecular Understanding and Modern Application of Traditional Medicines: Triumphs and Trials
    (2008-08-12) Corson, Timothy W.; Crews, Craig M
    Traditional medicines provide fertile ground for modern drug development, but first they must pass along a pathway of discovery, isolation, and mechanistic studies before eventual deployment in the clinic. Here, we highlight the challenges along this route, focusing on the compounds artemisinin, triptolide, celastrol, capsaicin, and curcumin.
  • Thumbnail Image
    Item
    Design and applications of bifunctional small molecules: Why two heads are better than one
    (2008-11-21) Corson, Timothy W.; Aberle, Nicholas; Crews, Craig M
    Induction of protein−protein interactions is a daunting challenge, but recent studies show promise for small molecules that specifically bring two or more protein molecules together for enhanced or novel biological effect. The first such bifunctional molecules were the rapamycin- and FK506-based “chemical inducers of dimerization”, but the field has since expanded with new molecules and new applications in chemical genetics and cell biology. Examples include coumermycin-mediated gyrase B dimerization, proteolysis targeting chimeric molecules (PROTACs), drug hybrids, and strategies for exploiting multivalency in toxin binding and antibody recruitment. This Review discusses these and other advances in the design and use of bifunctional small molecules and potential strategies for future systems.
  • Thumbnail Image
    Item
    Triptolide Directly Inhibits dCTP Pyrophosphatase
    (2011-07) Corson, Timothy W.; Cavga, Hüseyin; Aberle, Nicholas; Crews, Craig M
    Triptolide is a potent natural product, with documented antiproliferative, immunosuppressive, anti-inflammatory, antifertility, and antipolycystic kidney disease effects. Despite a wealth of knowledge about the biology of this compound, direct intracellular target proteins have remained elusive. We synthesized a biotinylated photoaffinity derivative of triptolide, and used it to identify dCTP pyrophosphatase 1 (DCTPP1) as a triptolide-interacting protein. Free triptolide interacts directly with recombinant DCTPP1, and inhibits the enzymatic activity of this protein. Triptolide is thus the first dCTP pyrophosphatase inhibitor identified, and DCTPP1 is a biophysically validated target of triptolide.
  • Thumbnail Image
    Item
    The TAg-RB Murine Retinoblastoma Cell of Origin Has Immunohistochemical Features of Differentiated Müller Glia with Progenitor Properties
    (2011-09) Pajovic, Sanja; Corson, Timothy W.; Spencer, Clarellen; Dimaras, Helen; Orlic-Milacic, Marija; Marchong, Mellone N; To, Kwong-Him; Thériault, Brigitte; Auspitz, Mark; Gallie, Brenda L
    PURPOSE: Human retinoblastoma arises from an undefined developing retinal cell after inactivation of RB1. This is emulated in a murine retinoblastoma model by inactivation of pRB by retinal-specific expression of simian virus 40 large T-antigen (TAg-RB). Some mutational events after RB1 loss in humans are recapitulated at the expression level in TAg-RB, supporting preclinical evidence that this model is useful for comparative studies between mouse and human. Here, the characteristics of the TAg-RB cell of origin are defined. METHODS: TAg-RB mice were killed at ages from embryonic day (E)18 to postnatal day (P)35. Tumors were analyzed by immunostaining, DNA copy number PCR, or real-time quantitative RT-PCR for TAg protein, retinal cell type markers, and retinoblastoma-relevant genes. RESULTS: TAg expression began at P8 in a row of inner nuclear layer cells that increased in number through P21 to P28, when clusters reminiscent of small tumors emerged from cells that escaped a wave of apoptosis. Early TAg-expressing cells coexpressed the developmental marker Chx10 and glial markers CRALBP, clusterin, and carbonic anhydrase II (Car2), but not TuJ1, an early neuronal marker. Emerging tumors retained expression of only Chx10 and carbonic anhydrase II. As with human retinoblastoma, TAg-RB tumors showed decreased Cdh11 DNA copy number and gain of Kif14 and Mycn. It was confirmed that TAg-RB tumors lose expression of tumor suppressor cadherin-11 and overexpress oncogenes Kif14, Dek, and E2f3. CONCLUSIONS: TAg-RB tumors displayed molecular similarity to human retinoblastoma and origin in a cell with features of differentiated Müller glia with progenitor properties.
  • Thumbnail Image
    Item
    Should Men and Women be Managed Differently in Glaucoma?
    (Springer, 2012) Abrams Tobe, Leslie; Harris, Alon; Trinidad, Jake; Chandrasekhar, Kaarthik; Cantor, Adam; Abrams, John; Amireskandari, Annahita; Siesky, Brent; Ophthalmology, School of Medicine
    Introduction: To assess differences in associations of ocular perfusion pressure (OPP) as well as retinal and retrobulbar blood flow between men and women with primary open angle glaucoma (OAG). Methods: A total of 116 patients with OAG (age 66.9 ± 10.9 years, 70 females) participating in the Indianapolis Glaucoma Progression Study were assessed for OPP, retinal microcirculation, and retrobulbar blood flow. Confocal scanning laser Doppler flowmetry measured peripapillary retinal capillary blood flow. Color Doppler imaging measured peak systolic (PSV) and diastolic blood flow velocities and vascular resistance in the ophthalmic (OA), central retinal (CRA), and nasal and temporal short posterior ciliary arteries (N/T PCA). Bivariate Spearman correlation and multivariate linear regression analyses were performed. Results: In female patients with OAG, inferior retinal capillary flow was associated with OPP (r = 0.246, P = 0.044). In men, superior and inferior sector retinal blood flow was associated with OPP (r = -0.402, P = 0.006 and r = -0.357, P = 0.016, respectively). There was no statistically significant association between OPP and retrobulbar blood vessel flow velocities in male patients with OAG but there was an association between OA and TPCA PSV and OPP in female patients with OAG (r = 0.290, P = 0.015 and r = 0.357, P = 0.002, respectively). In female patients with OAG, multivariate regression showed no statistically significant effect of any variable on the superior retinal capillary blood flow, with CRA PSV as a sole predictor to the inferior retinal sector (partial rho = 0.302, P = 0.015) and in male patients with OAG, superior sector retinal capillary blood flow was independently associated with intraocular pressure (partial rho = -0.371, P = 0.016) and OPP (partial rho = -0.456, P = 0.002) with a trend of association with OPP in the inferior retina (partial rho = -0.301, P = 0.053). Conclusions: There was a positive linear association between retinal microcirculation and OPP in females and a negative association in males. Male and female patients with OAG may differ in their vascular autoregulation in response to changes in OPP.
  • Thumbnail Image
    Item
    Small-Molecule Hydrophobic Tagging Induced Degradation of HaloTag Fusion Proteins
    (2012-02) Neklesa, Taavi K; Tae, Hyun Seop; Schneekloth, Ashley R; Stulberg, Michael J; Corson, Timothy W.; Sundberg, Thomas B; Raina, Kanak; Holley, Scott A; Crews, Craig M
    The ability to regulate any protein of interest in living systems with small molecules remains a challenge. We hypothesized that appending a hydrophobic moiety to the surface of a protein would mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation. We designed and synthesized bifunctional small molecules to bind a bacterial dehalogenase (the HaloTag protein) and present a hydrophobic group on its surface. Hydrophobic tagging of the HaloTag protein with an adamantyl moiety induced the degradation of cytosolic, isoprenylated and transmembrane HaloTag fusion proteins in cell culture. We demonstrated the in vivo utility of hydrophobic tagging by degrading proteins expressed in zebrafish embryos and by inhibiting Hras1G12V-driven tumor progression in mice. Therefore, hydrophobic tagging of HaloTag fusion proteins affords small-molecule control over any protein of interest, making it an ideal system for validating potential drug targets in disease models.
  • Thumbnail Image
    Item
    Delivery of Intraocular Triamcinolone Acetonide in the Treatment of Macular Edema
    (MDPI, 2012-03-15) Pickrell, Aaron; Harris, Alon; Ngo, Sandra; Amireskandari, Annahita; Stewart, Erin; Siesky, Brent; Ophthalmology, School of Medicine
    Macular edema (ME) is one of the eventual outcomes of various intraocular and systemic pathologies. The pathogenesis for ME is not yet entirely understood; however, some of the common risk factors for its development have been identified. While this investigation will not discuss the numerous etiologies of ME in detail, it appraises the two most widely studied delivery modalities of intraocular corticosteroids in the treatment of ME—intravitreal injection (IVI) and sub-Tenon’s infusion (STI). A thorough review of the medical literature was conducted to identify the efficacy and safety of IVI and STI, specifically for the administration of triamcinolone acetonide (TA), in the setting of ME in an attempt to elucidate a preferred steroid delivery modality for treatment of ME.
  • Thumbnail Image
    Item
    Comparison of Intraocular Pressure, Blood Pressure, Ocular Perfusion Pressure and Blood Flow Fluctuations During Dorzolamide Versus Timolol Add-On Therapy in Prostaglandin Analogue Treated Glaucoma Subjects
    (MDPI, 2012-03-21) Januleviciene, Ingrida; Siaudvytyte, Lina; Diliene, Vaida; Barsauskaite, Ruta; Paulaviciute-Baikstiene, Daiva; Siesky, Brent; Harris, Alon; Ophthalmology, School of Medicine
    Objective: To compare the effects of dorzolamide and timolol add-on therapy in open-angle glaucoma (OAG) patients previously treated with prostaglandin analogue (Pg), by evaluating fluctuations in the intraocular (IOP), blood (BP), ocular perfusion pressures (OPP) and retrobulbar blood flow (RBF) parameters. Methods: 35 OAG patients (35 eyes), 31 women (88.6%) age 63.3 (8.9) years were evaluated in a 3 month randomized, cross-over, single-masked study. During the experiments BP, heart rate, IOP and OPP were assessed 4 times per day (8-12-16-20 h). RBF was measured twice per day (8-20 h) using Color Doppler imaging in the ophthalmic (OA), central retinal (CRA), nasal (nSPCA) and temporal (tSPCA) posterior ciliary arteries. In each vessel, peak systolic velocity (PSV) and end-diastolic velocity (EDV) were assessed and vascular resistance (RI) calculated. Results: Both add-on therapies lowered IOP in a statistically significant manner from 15.7 ± 2.4 mmHg at latanoprost baseline to 14.9 ± 2.2 mmHg using dorzolamide (p < 0.001) and 14.2 ± 1.9 mmHg using timolol (p < 0.001). The IOP lowering effect was statistically significant at 20 h, favoring timolol as compared to dorzolamide (1.4 ± 2.4 vs. 0.2 ± 2.1 mmHg), (p < 0.05). Dorzolamide add-on therapy showed smaller IOP (2.0 ± 1.4), SPP (13.3 ± 7.9), systolic BP (13.5 ± 8.7) and diastolic BP (8.4 ± 5.4) fluctuations as compared to both latanoprost baseline or timolol add-on therapies. Higher difference between morning and evening BP was correlated to decreased evening CRA EDV in the timolol group (c = -0.41; p = 0.01). With increased MAP in the morning or evening hours, we found increased evening OA RI in timolol add-on group (c = 0.400, p = 0.02; c = 0.513, p = 0.002 accordingly). Higher MAP fluctuations were related to impaired RBF parameters during evening hours-decreased CRA EDV (c = -0.408; p = 0.01), increased CRA RI (c = 0.576; p < 0.001) and tSPCA RI (c = 0.356; p = 0.04) in the dorzolamide group and increased nSPCA RI (c = 0.351; p = 0.04) in the timolol add-on group. OPP fluctuations correlated with increased nSPCA RI (c = 0.453; p = 0.006) in the timolol group. OPP fluctuations were not related to IOP fluctuations in both add-on therapies (p < 0.05). Conclusions: Both dorzolamide and timolol add-on therapies lowered IOP in a statistically significant fashion dorzolamide add-on therapy showed lower fluctuations in IOP, SPP and BP. Higher variability of daytime OPP led to impaired RBF parameters in the evening.
  • Thumbnail Image
    Item
    The Effect of Diluted Penetration Enhancer in Nebulized Mist versus Liquid Drop Preparation Forms on Retrobulbar Blood Flow in Healthy Human Subjects
    (MDPI, 2012-08-08) Primus, Sally; Januleviciene, Ingrida; Siesky, Brent; Gerber, Austin; Egan, Patrick; Amireskandari, Annahita; Siaudvytyte, Lina; Barsauskaite, Ruta; Harris, Alon; Ophthalmology, School of Medicine
    The aim of this study was to compare the effects of nebulized mist and liquid drop applications on retrobulbar blood flow. A prospective, non-randomized clinical trial was used to collect data from 40 healthy human eyes. Color Doppler Imaging determined peak systolic (PSV) and end diastolic (EDV) blood flow velocities and resistance index (RI) in the ophthalmic artery after both applications. Measurements were taken at baseline and at 1 min post-treatment in both eyes with 5 min measurements in the treatment eye only. p values ≤ 0.05 were considered statistically significant. Mist application to treatment eye produced an increase in 1 min and 5 min PSV and EDV (0.001 < p < 0.03) and a decrease in 5 min RI (p = 0.01), with no significant changes in PSV, EDV or RI of control eye or in treatment eye 1 min RI (p > 0.05). Drop application to treatment eye produced an increase in PSV (p < 0.001) and EDV (p = 0.01) at 1 min, with an increase in control eye 1 min PSV and EDV (p = 0.03). There were no statistically significant changes in treatment eye PSV, EDV and RI after 5 min (p > 0.05). The use of nebulized mist may provide an effective alternative to liquid drop medication application.
  • Thumbnail Image
    Item
    Selective Bacteriophage Screening Targeting GαqQ209L Protein
    (Office of the Vice Chancellor for Research, 2013-04-05) Khan, Abdul Karim; Sishtila, Kamakshi; Corson, Timothy W.
    Uveal melanoma is the most common intraocular cancer in adults with 2,500 patients diagnosed every year in the United States The cancer is highly chemoersistant and is able to metastasize to other parts of the body, usually the liver where it proves almost universally fatal. It is often difficult to detect the growth of the tumor without a confirmatory biopsy. The goal of this project is to find a peptide sequence specifically binding to GαqQ209l which is an oncogenic mutation causing uveal melanoma in majority of all oncogenic cases. The method of bacteriophage display was used to find a peptide ligand that will bind specifically to the Gαq Q209L; subtractive panning was used against Gαq Wild Type and glutathion. The binders were amplified and then tested using a phage ELISA. This experiment is still in progress and there are no conclusions to be made yet. In the future it is hoped to successfully find a peptide sequence that is specific to cells.