Peter S. Reinach | State University of New York - Estados Unidos

• Grant number: 08/09578-7
• Support Opportunities: Research Grants - Visiting Researcher Grant - International
• Start date: June 01, 2009
• End date: June 14, 2010
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Igor Polikarpov
• Grantee: Igor Polikarpov
• Visiting researcher: Peter S. Reinach
• Visiting researcher institution: State University of New York, Oswego (SUNY), United States
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

Corneal epithelial layer renewal maintains tight junctions integrity between neighboring cells in the superficial layers, which is required for protecting the underlying tissue from from ambient pathogen infections. Otherwise pathogenic infiltration could cause inflammation and lead to losses corneal transparency and even blindness. Cellular renewal process is controlled by numerous different cytokines expressed by the lacrimal gland and cornea. One of the factors involved in cornea cellular renewal is epidermal growth factor (EGF). It induces control over cell proliferation and migration, which are responses underlying cellular renewal via interactions with its cognate receptor EGFR. Recently we discovered that EGFR also mediates such responses through transactivation by a different corneal epithelial receptor. This interaction with EGFR is a consequence of stimulation by transient receptor potential, TRPV1. This receptor, when stimulated by one of its agonists, capsaicin, also increases proliferation and epithelial migration. Even though TRPV1 receptor stimulation induces two of the same responses induced by EGFR through activation of its linked cell signaling pathways, TRPV1 also elicits increases in proinflammatory cytokines. In vivo in mice, we found that injury-induced TRPV1 stimulation elicits increases in proinflammatory cytokine release. This causes corneal clouding, ulceration and hemorrhaging, which can be suppressed by treatment of these mice with TRPV1 antagonists. This disconnect between EGF and capsaicin-induced suggests that capsaicin interacts with other receptors besides TRPV1. One candidate is the peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-dependent transcription factors, which belong to the nuclear receptor family. PPAR subfamily. They consist of three members: PPAR-alpha, PPAR-beta/delta and PPAR-gamma. These receptors modulate genes involved in inflammatory processes, including skin regeneration and reproduction. Within the scope of this project, we propose to study structure-functional relationships of PPAR-gamma with capsaicin since this receptor subtype mediates specifically control of inflammation in the cornea. Such an undertaking would contribute to a better comprehension of the mechanism of PPAR-gamma activation by capsaicin. Furthermore, it can help explain how two different types of cornea epithelial receptors mediate different responses, while being induced by some of the same cellular signaling pathways. This effort can help in the rational design of new pharmaceuticals which would suppress corneal inflammation while promoting stimulating proliferation and migraiton of epithelial cells. Such an outcome could be of great benefit in the clinical setting because TRPV1 agonists could be used to hasten epithelial wound healing in response to injury caused by environmental stresses that include exposure to injurious chemicals in the work place. At the same time, treatment with a novel TRPV1 agonist would not induce corneal inflammation. This is very beneficial because normal vision would ultimately not be compromised due to more rapid restoration of corneal transparency. (AU)