THE ROLE OF DIPEPTIDYL PEPTIDASE I IN THE REGULATION OF MAST CELL TRYPTASE

Apoptosis occurs under a variety of physiological and pathological conditions. It is essential for maintaining the homeostasis of the skin, and inappropriate apoptosis has been implicated in the pathogenesis of a multitude of skin disorders. Apoptosis mediates the decrease in cellularity during the transition between granulation to scar tissue, and aberrant apoptosis during wound healing has been attributed to the development of hypertrophic scars and keloids. Apoptosis may protect against the development of UV-induced skin cancer by selectively destroying sun-damaged keratinocytes. Mutations in the components of the surveillance machinery, such as p53 and bd-2, provide cells with an opportunity to escape from apoptosis and develop into nonmelanoma skin cancers. Early onset of apoptosis has been observed in diabetic wounds, contributing to blunted wound healing. Thus, manipulations which alter the onset or extent of apoptosis can potentially provide therapeutic interventions for the treatment of a variety of skin diseases. It is therefore important to delineate the molecular pathways and regulation of this multistep process. In this grant, I propose to use a variety of ways to manipulate the actin cytoskeleton and determine how actin remodeling contributes to UV- induced apoptosis in keratinocytes. I will examine the role of gelsolin, a Ca2+-activated actin filament severing protein which is recently identified as a direct and predominant substrate of caspase-3, in UVB-mediated apoptosis. This project is a new direction for my laboratory, but is very appropriate and timely because very little is known about the involvement of the actin cytoskeleton in apoptosis, even though the cytoskeleton is an important structural and regulatory machine. Its derangement is likely to contribute to the pathophysiological of many skin diseases. We have the tools and expertise to investigate this very important basic biological problem, and anticipate that our findings will suggest novel approaches for the treatment/or prevention of many skin diseases.