Corneal Expression and Function of Slurp1

Summary

Principal Investigator: SHIVALINGAPPA KOTTUR SWAMYNATHAN
Abstract: DESCRIPTION (provided by applicant): Though the secreted Ly6/urokinase type plasminogen activator receptor (uPAR) related protein-1 (Slurp1) is one of the most abundantly expressed proteins in the cornea and is secreted into the tear film, its biological function in the ocular surface is unknown. In this project, we test the central hypothesis that Slurp1 is a key immunomodulatory molecule that suppresses inflammation at the ocular surface and is downregulated in pro-inflammatory conditions. This hypothesis is supported by our exciting preliminary data demonstrating that Slurp1 expression is (i) increased upon mouse eyelid opening when the cornea is first exposed to the environment, (ii) abrogated within 24h of bacterial lipopolysaccharide (LPS) injection or Herpes Simplex Virus type-1 (HSV-1) infection concurrent with neutrophil infiltration, (iii) decreased in the inflamed Klf4-conditional null (Klf4CN) corneas, and (iv) suppressed by pro-inflammatory interleukins IL-4 and IL-13. More importantly, (a) over-expression of Slurp1 hindered the neutrophil influx in adenoviral keratitis and (b) Slurp1 bound the uPAR ligand uPA, suggesting that Slurp1 inhibits inflammation by competitive binding of UPAR ligands. We will test our hypothesis by pursuing three Specific Aims. In Aim 1, we will establish the corneal function of Slurp1. We will determine whether reduced expression of Slurp1 is a common theme in corneal inflammation by monitoring its expression in several different experimental models. By utilizing molecular approaches to decrease or increase mouse corneal expression of Slurp1, we will determine whether these changes augment or mitigate inflammation respectively. In Aim 2, we will examine the molecular mechanisms underlying Slurp1 functions. We will determine whether Slurp1 competes with uPAR for binding to its ligands uPA, vitronectin, and integrins, resulting in decreased neutrophil migration. In Aim 3, we will interrogate the molecular events governing regulation of Slurp1 expression in healthy and inflamed corneas. We will determine if Kruppel-like transcription factor-4 (Klf4) governs the increased expression of Slurp1 upon eyelid opening, and reactive oxygen species produced in response to different stimuli suppress Slurp1 in pro-inflammatory conditions. This project, based on the novel idea that Slurp1 is a molecular switch that suppresses chronic inflammation when present in normal levels and is downregulated in pro-inflammatory conditions will generate valuable new information related to ocular surface health and disease. It makes innovative use of our unique mouse models to expand knowledge of the interface between gene regulation and innate immune response and establishes a new paradigm explaining regulation of inflammation at the ocular surface. The anticipated outcomes will define a novel target for therapeutic intervention in managing inflammatory disorders of the ocular surface.
Funding Period: 2013-08-01 - 2017-07-31
more information: NIH RePORT

Research Grants

  1. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
  2. ADAPTATIONS TO HYPOXIA
    Kurt R Stenmark; Fiscal Year: 2013
  3. VASCULAR RELATIONS OF BLOOD CELLS AND PROTEINS
    Richard E Waugh; Fiscal Year: 2013
  4. DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESIS
    Stuart H Orkin; Fiscal Year: 2013
  5. Transplant Tolerance in Non-Human Primates
    STUART JOHNSTON KNECHTLE; Fiscal Year: 2013
  6. TH17 Autoimmunity to Type V Collagen in Heart and Lung Transplant
    David S Wilkes; Fiscal Year: 2013
  7. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
  8. Pathogenesis of Fungal Keratitis
    Eric Pearlman; Fiscal Year: 2013
  9. Pathogenesis and Diagnosis of Multiple System Atrophy (P01)
    Phillip A Low; Fiscal Year: 2013
  10. Four-Dimensional Heterogeneity of Fluid Phase Biopsies in Cancer (4DB-Center)
    Peter Kuhn; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  2. ADAPTATIONS TO HYPOXIA
    Kurt R Stenmark; Fiscal Year: 2013
    ..abstract_text> ..
  3. VASCULAR RELATIONS OF BLOOD CELLS AND PROTEINS
    Richard E Waugh; Fiscal Year: 2013
    ..The underlying mechanisms for these involve mechanical forces, molecular interactions and cellular properties acting synergistically in ways that are uniquely addressed by this program. ..
  4. DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESIS
    Stuart H Orkin; Fiscal Year: 2013
    ..abstract_text> ..
  5. Transplant Tolerance in Non-Human Primates
    STUART JOHNSTON KNECHTLE; Fiscal Year: 2013
    ..This goal will be accomplished via four interrelated projects and two supporting cores. ..
  6. TH17 Autoimmunity to Type V Collagen in Heart and Lung Transplant
    David S Wilkes; Fiscal Year: 2013
    ..abstract_text> ..
  7. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  8. Pathogenesis of Fungal Keratitis
    Eric Pearlman; Fiscal Year: 2013
    ..Results of these studies will further our understanding of the role of PMN-17 cells in fungal keratitis and identify novel targets for anti-inflammatory intervention to limit tissue damage in the cornea. ..
  9. Pathogenesis and Diagnosis of Multiple System Atrophy (P01)
    Phillip A Low; Fiscal Year: 2013
    ..The study will be conjointly carried out by Projects 1 and 4 and supported by Core A. These projects will continue to be supported by 3 cores. ..
  10. Four-Dimensional Heterogeneity of Fluid Phase Biopsies in Cancer (4DB-Center)
    Peter Kuhn; Fiscal Year: 2013
    ..The 4DB Center will also serve to disseminate information, education, and training to a new generation of cancer physicists;a generation that will implement the power of physics to conquer the problems of cancer. ..
  11. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  12. Peptide-based nanoparticle inhibition of CCR3-mediated inflammatory cell recruitm
    Vadim V Gaponenko; Fiscal Year: 2013
    ..The proposed project is highly likely to significantly impact the general approach to the development of novel asthma therapeutics. ..
  13. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  14. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  15. Medicinal Chemistry Based Optimization of Lead Compounds Against Multiple Scleros
    Antonio J Barbosa; Fiscal Year: 2013
    ..The studies proposed here will lead to the development of novel therapeutic agents for treating MS in humans. ..
  16. New Approaches To Cardiothoracic Tolerance Induction
    Joren C Madsen; Fiscal Year: 2013
    ..We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. ..
  17. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  18. Indiana University Center for Pediatric Pharmacology
    Jamie L Renbarger; Fiscal Year: 2013
    ..The direct outcome of these studies will be new biomarkers and predictive signatures that will increase the precision of the existing dosing schemas used in the treatment of childhood cancer. ..
  19. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
  20. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  21. Cell Adhesion Mechanisms in Vascular Disease &Thrombosis
    MARK HOWARD GINSBERG; Fiscal Year: 2013
    ..abstract_text> ..
  22. Novel Molecular Mechanisms Promote GPCR-Induced Bronchodilation in Asthma
    REYNOLD ALEXANDER PANETTIERI; Fiscal Year: 2013
    ..abstract_text> ..
  23. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  24. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..
  25. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..