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Document Type

Dissertation - University Access Only

Award Date

2014

Degree Name

Doctor of Philosophy (PhD)

Department / School

Pharmaceutical Sciences

First Advisor

G. Chandrasekhar

Abstract

Cornea, the smooth and crystal clear structure that encloses the front of eyeball is most susceptible to injuries due to its anatomic location.Accidental abrasions/scrapes, household chemicals, physical blows and UV radiation can easily inflict serious injury to the corneal epithelial layer.Delay in the repair of damaged epithelium could lead to hazed vision, scarring, infections leading and permanent vision loss. Several growth factors and extracellular matrix proteins (ECMs) are secreted at the wound site to facilitate the healing process.These factors regulate many intracellular signal mediators including Cdc42, a Rho family of small GTPase protein during wound healing process. The research present in this thesis reveals how Cdc42 signaling is important in cell migration and cell cycle propagation to promote wound healing and how growth factors and ECM proteins influence Cdc42 signaling in corneal epithelial cells.List of various materials and chemicals as well as methods employed to accomplish this project are presented in Chapter 2. Results presented in Chapter 3 suggests that to promote healing, Cdc42 may interact with receptor tyrosine kinase–activated signaling cascades that participate in cell migration and cell cycle progression.In chapter 4, the results on ECM protein-induced expression of various cell cycle proteins including Cdc42 are presented.The conclusion from this study is ECM- and growth factor receptor-mediated signals converge on Cdc42 to promote corneal epithelial cell proliferation. The results presented in chapter 5 validate the in vitro cell culture data that revealed the increased expression of these proteins in the presence of ECMs and growth factors.The results presented also indicate differential effects of HGF and KGF on corneal epithelial cell survival and regeneration. In chapter 6 the applicability of different pharmaceutical methods for the delivery of wound healing promoting agents to the corneal tissue was assessed. The overall conclusion of this research work is that the coordinated activation of integrin and tyrosine kinase receptors generates a signaling cross-talk that modulates Cdc42 action on cell cycle proteins and that plays a critical role in epithelium regeneration during wound repair.The interactions of Cdc42 with cell cycle progressing and arresting molecules are the driving forces that contribute to increased cell proliferation and growth required to restore and maintain the multilayer organization. Any alterations in Cdc42 expression and signaling could impact wound repair process.

Library of Congress Subject Headings

Cornea -- Wounds and injuries
Wound healing
Rho GTPases
Epithelial cells

Description

Includes bibliographical references (pages 180-219)

Format

application/pdf

Number of Pages

239

Publisher

South Dakota State University

Rights

In Copyright - Non-Commercial Use Permitted
http://rightsstatements.org/vocab/InC-NC/1.0/

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