Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. In nearly all tissues, there is a continual turnover of cells, usually by the process of apoptosis. In healthy tissues, the dying cells are quickly recognized and cleared by phagocytes. However, failure to promptly clear apoptotic cells leads to their secondary necrosis, release of toxic cytoplasmic contents, and inflammation within tissues. Current evidence suggests that the apoptotic cells `advertise'their presence early on in the death process, via soluble factors termed `find-me signals'to attract phagocytes, and thereby promote their prompt clearance. Initial studies from the Principal Investigators of this proposal have identified the nucleotides ATP and UTP as one type of `find-me signal'that is critical for apoptotic cell clearance in vitro and in vivo;subsequent studies led to a key discovery that the membrane protein pannexin 1 (Panx1) is the channel mediating nucleotide release from apoptotic cells. The overall hypothesis tested in this proposal is that pannexin channel-dependent release of nucleotide find-me signal from apoptotic cells, and subsequent sensing by phagocytes is important for proper cell clearance in vivo, and that disruption of the Panx1-mediated find-me signal pathway would contribute to diseases. Based on our preliminary studies, in Aim 1, we study the molecular basis of a novel Panx1 activation mechanism, seeking new understanding that will allow manipulation of `find- me` signal release via these channels.
In Aim 2, we use conditional cell-specific Panx1 knockout mice and conditional transgenic mice to determine if manipulation of Panx1 channels affects cell clearance in vivo. For this, we take advantage of a model where evidence suggests cell clearance is important in normal tissue homeostasis and in disease i.e., thymic development. Collectively, we expect these studies to yield new mechanistic understanding on how the regulated release of find-me signals influence cell clearance, and better define this mode of inter-cellular communication between dying cells and phagocytes, with implications for autoimmunity. These studies can also provide a rationale for considering Panx1 channels as a suitable target for therapeutic development.

Public Health Relevance

Failure to promptly clear dying cells in tissues has been linked to many diseases including autoimmunity, and lung inflammation. This proposal aims to provide new mechanistic understanding on how the regulated release of find-me signals from the dying cells mediate attraction of phagocytes, and in turn, influence cell clearance, with implications for inflammation. The results from the proposed studies may also help selective and beneficial pharmacological targeting of pannexin channels in promoting cell clearance in vivo.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Schools of Medicine
United States
Zip Code
Chiu, Yu-Hsin; Schappe, Michael S; Desai, Bimal N et al. (2018) Revisiting multimodal activation and channel properties of Pannexin 1. J Gen Physiol 150:19-39
Chiu, Yu-Hsin; Jin, Xueyao; Medina, Christopher B et al. (2017) A quantized mechanism for activation of pannexin channels. Nat Commun 8:14324
Weaver, Janelle L; Arandjelovic, Sanja; Brown, Gregory et al. (2017) Hematopoietic pannexin 1 function is critical for neuropathic pain. Sci Rep 7:42550
Elliott, Michael R; Ravichandran, Kodi S (2016) The Dynamics of Apoptotic Cell Clearance. Dev Cell 38:147-60
Lee, Chang Sup; Penberthy, Kristen K; Wheeler, Karen M et al. (2016) Boosting Apoptotic Cell Clearance by Colonic Epithelial Cells Attenuates Inflammation In Vivo. Immunity 44:807-20
Medina, C B; Ravichandran, K S (2016) Do not let death do us part: 'find-me' signals in communication between dying cells and the phagocytes. Cell Death Differ 23:979-89
Penberthy, Kristen K; Ravichandran, Kodi S (2016) Apoptotic cell recognition receptors and scavenger receptors. Immunol Rev 269:44-59
Ariel, Amiram; Ravichandran, Kodi S (2016) 'This way please': Apoptotic cells regulate phagocyte migration before and after engulfment. Eur J Immunol 46:1583-6
Arandjelovic, Sanja; Ravichandran, Kodi S (2015) Phagocytosis of apoptotic cells in homeostasis. Nat Immunol 16:907-17
Atkin-Smith, Georgia K; Tixeira, Rochelle; Paone, Stephanie et al. (2015) A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure. Nat Commun 6:7439

Showing the most recent 10 out of 16 publications