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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM107848-02
Application #
8730208
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Dunsmore, Sarah
Project Start
2013-09-10
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$300,200
Indirect Cost
$110,200
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Penberthy, Kristen K; Ravichandran, Kodi S (2016) Apoptotic cell recognition receptors and scavenger receptors. Immunol Rev 269:44-59
Elliott, Michael R; Ravichandran, Kodi S (2016) The Dynamics of Apoptotic Cell Clearance. Dev Cell 38:147-60
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
Billaud, Marie; Chiu, Yu-Hsin; Lohman, Alexander W et al. (2015) A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells. Sci Signal 8:ra17
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
Lohman, Alexander W; Leskov, Igor L; Butcher, Joshua T et al. (2015) Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation. Nat Commun 6:7965
Poon, Ivan K H; Chiu, Yu-Hsin; Armstrong, Allison J et al. (2014) Unexpected link between an antibiotic, pannexin channels and apoptosis. Nature 507:329-34
Poon, Ivan K H; Lucas, Christopher D; Rossi, Adriano G et al. (2014) Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol 14:166-80
Chiu, Yu-Hsin; Ravichandran, Kodi S; Bayliss, Douglas A (2014) Intrinsic properties and regulation of Pannexin 1 channel. Channels (Austin) 8:103-9

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