Shivalingappa (Shiva) Swamynathan, PhD
Assistant Professor of Ophthalmology
Laboratory of Ocular Surface Development
University of Pittsburgh School of Medicine
Sudha Swamynathan (Research Technician)
In the mouse, following eye opening around 2 weeks after birth, cells in the 1-2 cell layered epithelium proliferate and differentiate to form a 4-5 cell layered stratified squamous epithelium by 20 days after birth. The mature corneal epithelium containing 5-8 cell layers is present by 6 to 8 weeks after birth. Krüppel-like transcription factors KLF4 and KLF5 are among the most abundant transcription factors in the mouse cornea. KLF4 and KLF5 share an identical DNA-binding domain and regulate a diverse array of critical cellular functions. Considering that Klf4-null and Klf5-null mice die before mature cornea is formed, we have resorted to conditional deletion of Klf4 and Klf5 gene in the surface ectoderm- derived tissues of the eye (lens, cornea, conjunctiva and eyelids) by mating Klf4-loxP or Klf5-loxP mice with Le-Cre mice. Klf4 conditional null (Klf4CN) and Klf5CN mice display normal viability and fertility, and a defective ocular surface. Detailed analysis of their ocular surface phenotype along with identification of the corneal and conjunctival KLF4-target genes as well as corneal KLF5-target genes provided new insights into the non-redundant roles of KLF4 and KLF5 in post-natal maturation of the ocular surface. We plan to pursue this line of work further to understand the molecular basis for diverse functions of KLF4 and KLF5 in maturation and maintenance of the ocular surface.
In a second line of research, we are investigating the functions of the secreted Ly6/urokinase plasminogen activator receptor-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 recent work demonstrated that Slurp1 expression is (i) increased upon mouse eyelid opening when the cornea is first exposed to the environment, (ii) critically dependent on the transcription factor KLF4, (iii) abrogated within 24 h of bacterial lipopolysaccharide injection or Herpes-Simplex-Virus Type-1 (HSV-1) infection concurrent with neutrophil infiltration, (iv) decreased in inflamed Klf4CN corneas, and (v) suppressed by pro-inflammatory cytokines IL-4, IL-13 and TNF-. More importantly, 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. We are pursuing this line of 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
- Swamynathan, S.K.* (2013). Ocular surface development and gene expression. J Ophthalmol. 2013: 103947. doi: 10.1155/2013/103947. PMID: 23533700
- 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). Kruppel-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
- Kozmik, Z., Swamynathan, S.K., Ruzickova, J., Jonasova, K., Paces, C., Vlcek, C., and Piatigorsky, J. (2008). Cubozoan crystallins: Evidence for convergent evolution of Pax regulatory sequences. Evol. Dev. 10: 52-61. PMID: 18184357
- Swamynathan, S.K. and Piatigorsky, J. (2007) Regulation of the mouse B-Crystallin and MKBP/HspB2 Promoter activities by shared and gene specific intergenic elements: The importance of context dependency. Int. J. Dev. Biol. 51: 689-700. PMID: 17939115
- 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
- Kanungo, J., Swamynathan, S.K., and Piatigorsky, J. (2004) Abundant corneal gelsolin in Zebrafish and the ‘Four-Eyed’ fish, Anableps anableps: Possible analogy with multifunctional lens crystallins. Experimental Eye Res. 79: 949-956. PMID: 15642334
- Swamynathan, S.K., Crawford, M.A., Robison Jr, W.G., Kanungo, J and Piatigorsky, J. (2003). Adaptive differences in the structure and macromolecular compositions of the air and water corneas of the four-eyed fish (Anableps anableps). FASEB Journal 17: 1996-2005. PMID: 14597669
- Kanungo, J., Kozmik, Z, Swamynathan, S.K., and Piatigorsky, J. (2003) Gelsolin is a dorsalizing factor in zebrafish. Proc. Natl. Acad. Sci. USA. 100: 3287-3292. PMID: 12629212
- Swamynathan, S.K. and Piatigorsky, J. (2002) Orientation-dependent influence of an intergenic enhancer on the regulation of transcription of the divergently transcribed mouse shsp/B-crystallin and MKBP/HSPB2 genes. J. Biol. Chem. 277: 49700-49706. PMID: 12403771
Shiva Swamynathan, PhD
EEINS-1025, 203 Lothrop St.
Pittsburgh, PA 15213