Principal Investigator

Michael R. Elliott, Ph.D. University of Rochester work Box 609 601 Elmwood Ave Rochester NY 14642 office: KMRB 3-9625 p 585-273-4793

Role of Apoptotic Cell Find-Me Signals in the Clearance of Apoptotic Cells

Identification of dying cells (TUNEL+) in the murine thymus along with cortical epithelial cells (cytokeratin).

Cells undergoing apoptosis can release soluble cues (find-me signals) that promote the recruitment of phagocytes in the initial stages of apoptotic cell clearance. Triphosphate nucleotides (ATP and UTP), acting via P2Y receptors on phagocytes, were recently identified as such a find-me cue. The release of ATP and UTP by early apoptotic lymphocytes occurs via a specific mechanism involving Pannexin 1 membrane channels. In addition to nucleotides, other factors released by apoptotic cells have been identified, although a thorough understanding of the significance of these factors on cell clearance and the immune response to apoptotic cells is lacking.

The overall goal of this project is to understand how cues released by dying cells influence the cell clearance process and how they impact the innate and adaptive immune response in the local tissue environment. There are several ongoing projects related to find-me signals, including understanding what factors are released and the mechanisms of this release. Also, studies are underway to understand the consequences of such release on phagocytic clearance and tissue function in normal and diseased tissues. To address these questions, multiple in vitro and genetic mouse model approaches are currently being employed.

1

Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, Park D, Woodson RI, Ostankovich M, Sharma P, Lysiak JJ, Harden TK, Leitinger N and Ravichandran KS. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461:282 (2009).

2

Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM, Lazarowski ER, Armstrong AJ, Penuela S, Laird DW, Salvesen GS, Isakson BE, Bayliss DA and Ravichandran KS. Pannexin 1 channels regulate 'find-me' signal release and selective plasma membrane permeability during apoptosis. Nature, 467:863 (2010).

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