Shivalingappa (Shiva) Swamynathan
Associate Professor of Ophthalmology
Laboratory of Ocular Surface Development
University of Pittsburgh School of Medicine
Sudha Swamynathan, Laboratory Manager
Anil Tiwari, PhD, Postdoctoral Associate
The adult corneal epithelium (CE) is continually renewed throughout life. The most superficial cells lost by desquamation are replaced by the underlying cells derived from the basal cells which differentiate as they migrate upwards, and in turn are replaced by the peripheral limbal stem cell-derived transient amplifying cells that migrate centripetally. We are interested in understanding the functions of Krüppel-like factors KLF4 and KLF5 that are among the most abundant transcription factors in the adult mouse cornea, in this process. As germline ablation of Klf4 or Klf5 results in premature lethality before mature cornea is formed, we resorted to Cre-Lox-mediated conditional ablation of Klf4 or Klf5 in the ocular surface from embryonic day-9 to study their role in CE maturation, or specifically within the normally formed adult CE in a spatiotemporally regulated manner to study their role in homeostasis. Our studies revealed that KLF4 and KLF5 have profound influence on the ocular surface by regulating CE cell proliferation, differentiation, structural stability, and barrier function, and conjunctival goblet cell formation. We are pursuing this work further to understand the molecular basis for diverse functions of KLF4 and KLF5 in maturation and maintenance of the ocular surface.
We are also investigating the ocular surface functions of the secreted Ly6/uPAR-related protein-1 (SLURP1), associated with the hyperkeratotic disorder Mal-de-Meleda. Slurp1 is one of the most abundantly expressed peptides in the mouse cornea and is secreted into the tear film. Our work demonstrated that Slurp1 expression is (i) increased upon mouse eyelid opening when the cornea is first exposed to the environment, (ii) dependent on the transcription factor KLF4, (iii) abrogated within 24 h of bacterial lipopolysaccharide injection or Herpes-Simplex-Virus (HSV) infection concurrent with neutrophil infiltration, (iv) decreased in inflamed Klf4CN corneas, and (v) suppressed by pro-inflammatory cytokines IL-4, IL-13 and TNF-a. Slurp1 expression was significantly reduced in adenoviral keratitis model of corneal inflammation, restoration of which restricted the neutrophilic infiltrate, providing convincing evidence in favor of an immunomodulatory role for Slurp1. Our recent work revealed that Slurp1 serves as a soluble scavenger of the urokinase receptor (uPAR) ligands such as urokinase (uPA), and that SLURP1 has an anti-angiogenic role in the transparent cornea. We are pursuing this work further to determine the value of SLURP1 as a target for developing novel therapeutic approaches for managing inflammatory disorders of the ocular surface.
We are interested in grooming scientists with a serious commitment to basic research in ocular surface development. Graduate student or Postdoctoral research fellow positions are available to study the molecular mechanisms of regulation of gene expression during ocular surface development. If interested, please contact the PI by email (Swamynathansk@upmc.edu) with your CV and a short summary of your research experience and goals.
Select Recent Publications
- Tiwari, A., Swamynathan, S., Alexander, N., Gnalian, J., Tian, S., Kinchington, P.R. and Swamynathan, S.K. (2019). KLF4 regulates corneal epithelial cell cycle progression by suppressing canonical TGF-b signaling and upregulating CDK inhibitors P16 and P27. Invest. Ophthalmol. Vis. Sci. 60(2):731-740. PMID: 30786277.
- Loughner, C.L., Tiwari, A., Kenchegowda, D., Swamynathan, S. and Swamynathan, S.K. (2017). Spatiotemporally controlled ablation of Klf5 results in dysregulated epithelial homeostasis in adult mouse corneas. Invest. Ophthalmol. Vis. Sci. 58(11):4683-4693. PMID: 28910443.
- Swamynathan, S., Loughner, C.L. and Swamynathan, S.K. (2017). Inhibition of HUVEC tube formation via suppression of NFB suggests an anti-angiogenic role for SLURP1 in the transparent cornea. Exp. Eye Res. 164:118-128. PMID: 28803936.
- Tiwari, A., Loughner, C.L., Swamynathan, S. and Swamynathan, S.K. (2017). KLF4 plays an essential role in corneal epithelial homeostasis by promoting epithelial cell fate and suppressing epithelial–mesenchymal transition. Invest. Ophthalmol. Vis. Sci. 58: 2785-2795. PMID: 28549095.
- Loughner, C.L., Bruford, E.A., McAndrews, M.S., Delp, E.E., Swamynathan, S. and Swamynathan, S.K. (2016). Organization, evolution and functions of the human and mouse Ly6/uPAR family genes. Human Genomics. doi: 10.1186/s40246-016-0074-2. PMID: 27098205
- Swamynathan, S., Delp, E.E., Harvey, S.A.K., Loughner, C.L., Raju, L. and Swamynathan, S.K. (2015) Corneal expression of SLURP-1 by age, sex, genetic strain and ocular surface health. Invest. Ophthalmol. Vis. Sci. 56:7888-7896. PMID: 26670825.
- Delp, E.E., Swamynathan, S., Kao, W.W. and Swamynathan, S.K. (2015). Spatiotemporally regulated ablation of Klf4 in adult mouse corneal epithelial cells results in altered epithelial cell identity and disrupted homeostasis. Invest. Ophthalmol. Vis. Sci. 56:3549-3558. PMID: 26047041
- Swamynathan, S. and Swamynathan, S.K. (2014). SLURP-1 modulates corneal homeostasis by serving as a soluble scavenger of urokinase-type plasminogen activator uPA. Invest. Ophthalmol. Vis. Sci. 55:6251-6261. PMID: 25168896.
- Swamynathan, S.K. (2013). Ocular surface development and gene expression. J Ophthalmol. 2013: 103947. doi: 10.1155/2013/103947. PMID: 23533700
- Gupta, D., Harvey, S.A., Kenchegowda, D., Swamynathan, S., and Swamynathan, S.K. (2013). Regulation of mouse lens maturation and gene expression by Krüppel-like factor 4. Exp. Eye Res. 116: 205-218. PMID: 24076321.
- Swamynathan, S., Buela, K.A, Kinchington, P., Misawa, H., Lathrop, K.L., Hendricks, R.L. and Swamynathan, S.K. (2012). Klf4 regulates the expression of Slurp1, which functions as an immunomodulatory peptide in the mouse cornea. Invest. Ophthalmol. Vis. Sci. 53:8433-8446. PMID: 23139280.
- Kenchegowda, D., Harvey, S.A.K., Swamynathan, S., Lathrop, K.L. and Swamynathan, S.K. (2012) Critical Role of Klf5 in Regulating Gene Expression during Post-Eyelid Opening Maturation of Mouse Corneas. PLoS ONE 7(9): e44771. doi:10.1371/journal. pone.0044771. PMID: 23024760.
- Kenchegowda, D, Swamynathan, S, Gupta, D, Wan, H, Whitsett, J, and Swamynathan S.K. 2011. Conditional disruption of mouse Klf5 results in defective eyelids with malformed meibomian glands, abnormal cornea and loss of conjunctival goblet cells. Dev. Biol. 356:5-18. PMID: 21600198.
- Gupta, D., Harvey, S.A., Kaminski, N. and Swamynathan, S.K. 2011. Mouse conjunctival forniceal gene expression during postnatal development and its regulation by Krüppel-like factor 4. Invest. Ophthalmol. Vis. Sci. 52:4951-4962. PMID: 21398290.
- Swamynathan, S., Kenchegowda, D., Piatigorsky, J. and Swamynathan, S.K. 2011. Regulation of the corneal epithelial barrier function by Krüppel-like transcription factor 4. Invest. Ophthalmol. Vis. Sci. 52:1762-1769. PMID: 21051695.
- Swamynathan, S.K. (2010). Krüppel-Like Factors: Three fingers in control. Human Genomics. 4(4): 1-8. PMID: 20511139
- Young, R.D., Swamynathan, S.K., Boote, C., Mann, M., Quantock, A.J., Piatigorsky, J., Funderburgh, J.L., and Meek, K.M. 2009. Stromal edema in Klf4 conditional null mouse cornea is associated with altered collagen fibril organization and reduced proteoglycans. Invest. Ophthalmol. Vis. Sci. 50:4155-4161. PMID: 19387067.
- Swamynathan, S.K., Davis, J. and Piatigorsky, J. (2008). Identification of candidate KLF4 target genes reveals the molecular basis of the diverse regulatory roles of KLF4 in the mouse cornea. Invest. Ophthalmol. Vis. Sci. 49: 3360-3370. PMID: 18469187.
- Swamynathan, S.K., Katz, J.P., Kaestner, K.H., Ashery-Padan, R., Crawford, M.A. and Piatigorsky, J. (2007) Conditional deletion of the mouse Klf4 gene results in corneal epithelial fragility, stromal edema, and loss of conjunctival goblet cells. Mol. Cell. Biol. 27: 182-194. PMID: 17060454.
Shiva Swamynathan, PhD
EEINS-1025, 203 Lothrop St.
Pittsburgh, PA 15213