Role of insulin-like growth factor binding proteins in the pathogenesis of herpes stromal keratitis.

胰岛素样生长因子结合蛋白在疱疹基质角膜炎发病机制中的作用。

• 批准号: 10056782
• 负责人: Susmit Suvas
• 金额: $ 37.74万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10056782
• 关键词: Ablation; Adrenal Cortex Hormones; Antiviral Agents; Biological Assay; Biological Availability; Blindness; Blocking Antibodies; Blood Circulation; Blood Vessels; Cataract; Cell Aging; Cell surface; Chronic; Clinical; Confocal Microscopy; Cornea; Corneal Stroma; Corneal edema; Development; Disease; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Event; Eye Infections; Glaucoma; Goals; Herpesvirus 1; Human; Hypoxia; Immunomodulators; Impaired wound healing; Infection; Inflammation; Inflammatory; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like Growth-Factor-Binding Proteins; Insulin-Like-Growth Factor I Receptor; Keratitis; Knock-out; Knockout Mice; Knowledge; Lesion; Leukocytes; Measures; Membrane; Molecular; Mus; Myelogenous; Myeloid Cells; Oral; Outcome; Outcome Measure; Pathogenesis; Phosphorylation; Physiologic Intraocular Pressure; Plasmids; Predisposition; Protein Array; Proteins; Publishing; Receptor Signaling; Recombinant Insulin-Like Growth Factor; Recurrence; Reporting; Risk; Role; Sampling; Severities; Somatomedins; Stains; Steroids; Tamoxifen; Testing; Time; Topical application; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation; United States; Vascular Endothelial Cell; Viral; Viral Load result; Virus Replication; Visual; angiogenesis; base; conditional knockout; corneal epithelium; density; experimental study; immunopathology; in vivo; mouse model; neovascularization; neutrophil; new therapeutic target; novel therapeutic intervention; pleiotropism; response; senescence

Herpes  stromal  keratitis  (HSK)  is  a  chronic  inflammatory  condition  that  develops  in  response  to  a  recurrent  corneal  infection  with  herpes  simplex  virus-­1  (HSV-­1).  HSK  is  the  leading  cause  of  infection-­induced  corneal  blindness  in  the  United  States.  Clinical  manifestation  of  HSK  involves  the  development  of  opacity  and  neovascularization into the avascular cornea. Newly formed leaky blood vessels in the corneal stroma obscure  the visual axis, traffic the leukocytes (mostly neutrophils) into the inflamed cornea, and cause the corneal edema.  The  current  mainstay  of  HSK  treatment  requires  the  long-­term  use  of  oral  antiviral  drugs  and  the  topical  application  of  steroids.  The  prolonged  use  of  topical  steroids  causes  a  predisposition  to  herpetic  reactivation,  cataract  development,  and  increased  intraocular  pressure  (IOP),  which  may  cause  the  development  of  glaucoma. A better understanding of cellular and molecular events involved in the pathogenesis of HSK could  provide  novel  therapeutic  targets  to  reduce  the  severity  of  HSK.  The  focus  of  this  application  is  to  understand  the mechanisms by which Insulin-­like growth factor binding protein-­3 (IGFBP-­3) regulates the pathogenesis of  HSK. IGFBP-­3 exerts its effect through insulin-­like growth factor (IGF)-­independent and-­dependent mechanisms.  In  an  IGF-­independent  manner,  IGFBP-­3  is  known  to  induce  cellular  senescence.  The  cellular  senescence  is  reported to inhibit viral replication. The IGF-­dependent activity of IGFBP-­3 involves sequestration of IGF-­1 and  IGF-­2  molecules  and  limiting  their  bioavailability  to  IGF-­1R,  and  thereby  regulates  IGF-­1R  signaling.  Our  preliminary results showed an elevated expression of IGFBP-­3 in HSV-­1 infected corneas of B6 mice, whereas  a  significantly  reduced  amount  of  IGFBP-­3  protein  was  detected  in  the  circulation  of  infected  B6  mice  when  compared  to  uninfected  B6  mice.  The  infected  corneas  of  IGFBP-­3  knockout  (IGFBP-­3  KO)  mice  showed  an  increased  viral  load.  Besides,  increased  phosphorylation  of  IGF-­1R,  the  first  step  in  IGF-­1R  signaling,  was  determined  in  leukocytes  infiltrating  the  HSK  developing  corneas  of  IGFBP-­3  KO  than  B6  mice.  A  significant  increase  in  hemangiogenesis  and  opacity  was  measured  in  infected  corneas  of  IGFBP-­3  KO  than  B6  mice.  Together,  these  results  led  us  to  hypothesize  that  IGFBP-­3  enhances  viral  clearance,  reduces  angiogenesis,  and  decreases  the  survival  and  effector  function  of  myeloid  cells  in  HSK  developing  corneas.  Therefore,  enhancing the IGFBP-­3 protein level in HSV-­1 infected cornea should alleviate the severity of HSK. Three aims  are proposed to test our hypothesis. Aim I will test the hypothesis that hypoxia enhances IGFBP-­3 expression  in corneal epithelial cells, and an increased level of IGFBP-­3 induces senescence in epithelial cells, and cellular  senescence  promotes  HSV-­1  clearance  from  the  infected  cornea.  Aim  II  will  test  the  hypothesis  that  IGF-­1R  signaling  in  myeloid  and  vascular  endothelial  cells  control  the  severity  of  HSK.  Aim  III  will  test  the  hypothesis  that increasing IGFBP-­3 protein in HSV-­1 infected cornea alleviates the severity of HSK.

疱疹间质性角膜炎（HSK）是一种慢性炎症，是对复发性角膜炎的反应