Grant: Project Grant

Organ fibrosis or progressive scarring of vital organs such as kidney, lung liver and heart is a failed healing attempt in response to chronic injury. Fibrosis is the final common pathway leading to organ failure in many common diseases including diabetes, hypertension, atherosclerosis and substance abuse. It is a striking but lesser known fact that fibrosis is a major component of mortality, being responsible for 45% of all deaths in the Western World. Despite its paramount medical importance, fibrosis has no cure; currently there are no means to stop or reverse the disease process and the only temporary hope is organ replacement therapy. It is therefore critically important to understand the molecular and cellular mechanisms that underlie the initiation and progression of organ fibrosis. Fibrosis-associated changes are brought about by altered gene expression in various cells. This is due to chemical and mechanical injury-induced activation of transcription factors. These factors need to travel to the cell's nucleus where they turn on target genes. However we do not understand how this process happens and how it can be inhibited or exploited to lessen fibrosis. Our previous work shows that cellular stress induces robust remodeling of the cell's skeleton (cytoskeleton), which may be a key regulator of the nuclear traffic of transcription factors. Therefore, the overall aim of my research is to understand the molecular and cell biological mechanisms underlying the general and cytoskeletal regulation of fibrosis-inducing transcription factors. We will use this knowledge to develop new antifibrotic molecular therapies, such as antifibrotic viruses to halt or reverse fibrosis. To achieve these goals we will create a new molecular toolkit to study and alter the traffic of transcription factors. In summary, these studies will provide fundamental insight into a new area of cell biology, and use the acquired knowledge to combat a common, currently incurable disease.