Background

Background, Inception of the Center, Mission & Goals

Background on apoptotic cell clearance:

·     Everyday, we turnover 100-200 billion cells in the body.  Generation of apoptotic cells and their turnover are part of a normal homeostasis in the bone marrow, thymus, eye, gut etc. More recently, several disease states such as autoimmunity (best example being Lupus), atherosclerosis, chronic inflammation and cancer have now been linked to failed or inadequate corpse clearance.  The apoptotic cell clearance mechanism has also been linked to axonal pruning and part of the response to neuronal injury.

·     While the process of apoptosis has been widely studied for the past 20 years, how you ‘get rid of these bodies’ has lagged behind. This is largely because we did not initially appreciate that cell death in a test tube could be different from cell death in vivo, i.e. cell death is closely coupled to rapid and efficient, and ‘immunologically quiet’ clearance of these corpses.  To put it another way, the field of apoptosis did not recognize the biological significance of this problem until the ‘garbage collection’ was interrupted (e.g. knockout mice with disruption of engulfment genes or human disease states).

·     Recently, the molecules and mechanisms involved in engulfment are beginning to be defined through a combination of genetics in C. elegans and Drosophila, mammalian cell line studies and mouse knockouts.  This has provided a great opportunity to begin to pick apart this problem both at the molecular level and whole organism level and in the context of human disease.

·     In the past two years ~15 papers have been published on this topic, just in Nature, Cell, Science, Nature Cell Biology and Immunity.  Thus, the apoptotic cell engulfment field is quite hot and perceived by the scientific community as having a large overall impact to many different areas.

 

Why have this Center for Cell Clearance?

·     Initially, work from the Ravichandran laboratory at the University of Virginia identified some of the key signaling molecules involved in apoptotic cell clearance and revealed their relevance in the context of mammals and C. elegans. Since then, several investigators at University of Virginia have also become interested in the problem of apoptotic cell clearance from different angles: such as cell clearance in the nervous system (Jim Mandell), apoptosis and its relevance to atherosclerosis (Leitinger and Ravichandran), turnover of cells in the gut and its relevance to inflammatory bowel disease (Peter Ernst and Ravichandran), insights on how amoeba can cause apoptosis and subsequently ingest these dying lymphocytes (Petri), clearance of apoptotic germ cells by Sertoli cells of the testes (Jeffrey Lyisak and Ravichandran), and addressing the importance of apoptotic cell clearance in autoimmunity (Ken Tung).  Thus, there is now a critical mass of investigators at the University of Virginia who would be benefited from a focused and more integrated research effort on the topic of apoptotic cell clearance.  Hence, the birth of this Center for Cell Clearance!

·     Besides those at UVA, investigators from other institutions in the field of apoptotic cell clearance have often expressed the view that there is a critical need to bring all of the investigators together.  While this is achieved every two years at a Gordon Conference dedicated to apoptotic cell clearance, the field is moving too fast and there needs to be a forum for communication between investigators. Dr. Kodi Ravichandran, who was a Vice Chair of the Gordon Research Conference in 2005 and Chair of the GRC meeting in 2007 has taken the lead to initiate this effort to help bring investigators from within and outside UVA through this Center for Cell Clearance.